Pyrrolopyrimidinone derivatives

ABSTRACT

A compound having GSK-3 inhibitory activity.  
                 
         A 1  and A 3  are a single bond, an aliphatic hydrocarbon group; A 2  and A 4  are a single bond, CO, COO, CONR, O, OCO, NR, NRCO, NRCOO, etc.; G 1  is a single bond, an aliphatic hydrocarbon, aromatic hydrocarbon, heterocyclic; G 2  is H, an aliphatic hydrocarbon, an alicyclic hydrocarbon, an aromatic hydrocarbon, heterocyclic; A 5  is a single bond, NR; R 2  is H, halogen, an aliphatic hydrocarbon, alicyclic hydrocarbon, aromatic hydrocarbon, heterocyclic; A 6  is a single bond, NR, CO, NRCO, NRCONR, CONR, COO, O, etc.; R 3  is H, halogen, nitro, saturated aliphatic hydrocarbon, alicyclic hydrocarbon, aromatic hydrocarbon, heterocyclic; and R 3  may be a trimethylsilyl, formyl, acyl, carboxyl, alkoxylcarbonyl, carbamoyl, alkylcarbamoyl, or cyano group when A 6  is CR═CR or C≡C, wherein R is H or an lower aliphatic hydrocarbon group.

TECHNICAL FIELD

The present invention relates to novel pyrrolopyrimidinone derivatives that have an action inhibiting glycogen synthase kinase-3 (GSK-3). More particularly, the invention relates to novel pyrrolo[3,2-d] pyrimidinone derivatives useful as pharmaceutical agents for treating and/or preventing disorders mediated by GSK-3 activity, particularly, impaired glucose tolerance, type I diabetes, type II diabetes, diabetic complications (retinopathy, nephropathy, neuropathy or great vessel hindrance), Alzheimer's disease, neurodegenerative diseases (AIDS encephalophy, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis), bipolar affective disorder (manic depressive psychosis), traumatic cerebrospinal injury, epilepsy, obesity, atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, alopecia, inflammatory diseases (arthrosis deformans, rheumatism, atopic dermatitis, psoriasis, ulcerative colitis, Crohn's disease, sepsis or systemic inflammatory response syndrome), cancer and immunodeficiency.

BACKGROUND ART

GSK-3 is a serine/threonine protein kinase. Two isoforms, i.e., α and β, which are encoded by distinct genes, have been identified (see Trends Biochem. Sci., 1991, Vol. 16, p. 177).

Both GSK-3 isoforms have a monomeric structure and are constitutively active in resting cells. GSK-3 was originally identified as a kinase that inhibits glycogen synthase by direct phosphorylation (see Eur. J. Biochem., 1980, Vol. 107, p. 519). Upon insulin activation, GSK-3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events, such as glucose transport. Also, it has been known that GSK-3 activity is inactivated by other growth factors, such as IGF-1 or FGF, through signaling from receptor tyrosine kinases (see Biochem. J., UK, 1993, Vol. 294, p. 625; Biochem. J., UK, 1994, Vol. 303, p. 21; Biochem. J., UK, 1994, Vol. 303, p. 27).

GSK-3 inhibitors are useful in the treatment of disorders that are mediated by GSK-3 activity. In addition, inhibition of GSK-3 mimics the activation of growth factor signaling pathways and consequently GSK-3 inhibitors are useful in the treatment of diseases in which such pathways are inactive. Examples of diseases that can be treated with GSK-3 inhibitors are described below.

Type I diabetes is induced due to autoimmune destruction of β cells as pancreatic insulin production cells, resulting in deficiency of insulin. From this, it is necessary for a type I diabetic patient to routinely be administered insulin for maintaining life. However, in current insulin therapy, strict control of the blood glucose levels like the ability of normal β cells cannot be reproduced. Thus, type I diabetes is liable to induce diabetic complications such as retinopathy, nephropathy, neuropathy, great vessels hindrance or the like.

Type II diabetes is a multifactorial disease. Hyperglycemia is due to insulin resistance in the liver, skeletal muscle and lipid tissues coupled with inadequate or defective secretion of insulin from pancreatic islets. As a result, diabetic complications such as retinopathy, nephropathy, neuropathy, or great vessels hindrance are induced. Skeletal muscle is the major site for insulin-stimulated glucose uptake, and glucose removed from the circulation is either metabolized through glycolysis and the TCA cycle or stored as glycogen. Muscle glycogen deposition plays a very important role in glucose homeostasis, and Type II diabetic subjects have defective muscle glycogen storage. GSK-3, which is known to phosphorylate glycogen synthase, inhibits the accumulation of glycogen in peripheral tissues and lowers the reactivity of insulin, leading to an increase in blood level of glucose.

Recently, it has been reported that the expression of GSK-3 is stimulated in skeletal muscles of type II diabetic patients, and the GSK-3α activity and insulin in skeletal muscles are inversely correlated (see Diabetes, USA, 2000, Vol. 49, p. 263). Where GSK-3β and active GSK-3β variants (S9A, S9E) are overexpressed in HEK-293 cells, the GSK activity is inhibited (see Proc. Natl. Acad. Sci., USA, 1996, Vol. 93, p. 10228). In CHO cells in which insulin receptor and insulin receptor substrate 1 (IRS-1) are expressed, overexpression of GSK-3β brings about a decrease in the insulin activity (see 8: Proc. Natl. Acad. Sci., USA, 1997, Vol. 94, 9660). Recent research carried out using C57BL/6J mice with pyknic type diabetes has clearly shown that GSK-3 activity stimulation and insulin resistance are correlated to the progress of type II diabetes (see Diabetes, USA, 1999, Vol. 48, p. 1662).

Conventionally, lithium salts have been known to have inhibitory effects of GSK-3 activity (see Proc. Natl. Acad. Sci., USA, 1996, Vol. 93, p. 8455). It has been reported that the therapy using the lithium salts lowers glucose levels in both type I and II diabetic patients, thereby alleviating the severity of the disease (see Biol. Trace Elements Res., 1997, Vol. 60, p. 131). However, lithium salts have also been found to exhibit various side effects on molecular targets other than GSK-3.

From the findings described above, it can be concluded that GSK-3 inhibitors are effective therapeutics for the treatment of impaired glucose tolerance, type I diabetes, type II diabetes and complications thereof.

It is also suggested that GSK-3 is associated with progress of Alzheimer's disease. The characteristic pathological features of Alzheimer's disease are senile plaques due to agglomeration of amyloid beta (Aβ) peptide and the formation of intracellular neurofibrillary tangles, leading to a large quantity of neuronal cell death, resulting in dementia. It is believed that GSK-3 involves abnormal phosphorylation of tau protein, which causes a neurofibrillary change in the course of progress of Alzheimer's disease (see Acta Neuropathol., 2002, Vol. 103, p. 91). Also, it has been found that GSK-3 inhibitors can prevent neuronal cell death (see J. Neurochem., 2001, Vol. 77, p. 94). Therefore, it is believed that the application of GSK-3 inhibitors to Alzheimer's disease can delay the progress of the disease. To date, therapeutic agents for Alzheimer's disease have mainly been used in conjunction with allopathy (see Expert Opin. Pharmacother., 1999, Vol. 1, p. 121). However, there is no known pharmaceutical agent that is effective in preventing neuronal cell death and delaying the onset or progress of Alzheimer's disease. These findings imply that GSK-3 inhibitors are effective pharmaceutical agents in alleviating the severity of Alzheimer's dementia.

There is a report that GSK-3 inhibitors suppress neuronal cell death, specifically, neuronal cell death due to overexcitement through glutamic acid (see Proc. Natl. Acad. Sci., USA, 1998, Vol. 95, p. 2642; J. Neurochem., 2001, Vol. 77, p. 94). This suggests that GSK-3 inhibitors are possibly useful in the treatment of bipolar affective disorder such as manic depressive psychosis, epilepsy or other degenerative brain injury or neurodegenerative diseases. Examples of the neurodegenerative disease include in addition to the Alzheimer's disease, AIDS encephalopathy, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Pick's disease, progressive supranuclear palsy and so on. Also, overexcitement through glutamic acid is presumably a principal cause of brain dysfunction in stroke, including cerebral infarction, intracerebral hemorrhage and subarachnoid hemorrhage, traumatic cerebrospinal injury, bacteria/virus infectious disease, and GSK-3 inhibitors are expected to be effectively used in the treatment of these diseases. All of such diseases accompany neuronal death. Currently, no therapeutic agents for effectively suppressing neuronal death are available. Therefore, GSK-3 inhibitors are believed to become potentially effective pharmaceutical agents for the treatment of various kinds of neurodegenerative diseases, dipolar affective disorders (manic-depressive psychosis), epilepsy, stroke, traumatic cerebrospinal injury, and the like.

Several in vitro research results have led to a report that Wint10B potently suppresses the differentiation of preadipocytes to mature fat cells (see Science, 2000, Vol. 289, p. 950). GSK-3 specific inhibitors mimic Wint10B signaling in preadipocytes, that is, GSK-3 specific inhibitors stabilize free β-catenin in cytoplasm and suppress the induction of C/EBPα and PPARγ, thereby suppressing the formation of fat (see J. Biol. Chem, 2002, Vol. 277, p. 30998). GSK-3 inhibitors are therefore potentially useful as effective pharmaceutical compositions for treating obesity.

Also, β-catenin has been known to be a GSK-3 substrate in vivo. After phosphorylation by GSK-3, β-catenin is subjected to proteosome-dependent degradation (see EMBO J., 1998, Vol. 17, p. 1371). Meanwhile, transient β-catenin stabilization may lead to increase hair development (see Cell, 1998, Vol. 95, p. 605). Consequently, GSK-3 inhibitors are believed to be a useful medicament for the treatment of alopecia.

Further, research into GSK-3β knock out mouse-derived fibroblasts implies that GSK-3β regulates the activity of transcription factor NFκB to be at a positive level (see Nature, 2000, Vol. 406, p. 86). NFκB is in charge of cell responsiveness to numerous inflammatory stimuli. Thus, GSK-3 inhibitors may have beneficial effects in the treatment of inflammatory diseases such as arthrosis deformans, rheumatism, atopic dermatitis, psoriasis, ulcerative colitis, Crohn's Disease, sepsis, or systemic inflammatory response syndrome, by adjusting the NFκB activity to be at a negative level.

A transcription factor NF-AT is dephosphorylated by calcineurine and increases immunosuppressive response (see Science, 1997, Vol. 275, p. 1930). Conversely, GSK-3 phosphorylates NF-AT and transports the same from nuclei, thereby suppressing the expression of initial immune response gene. Thus, GSK-3 inhibitors could be useful to immunity activation for cancer immunotherapy.

Examples of materials that have conventionally been known to have GSK-3 inhibiting activity include hymenialdisine derivatives (see Chemistry & Biology, 2000, Vol. 7, p. 51, and WO01/41768 pamphlet), maleiimide derivatives (see Chemistry & Biology, 2000, Vol. 7, p. 793), paullone derivatives (see Eur. J. Biochem., 2000, Vol. 267, p. 5983 and WO01/60374 Pamphlet), purine derivatives (see WO98/16528 Pamphlet), pyrimidine and pyridine derivatives (see WO99/65897 Pamphlet), hydroxyflavone derivatives (see WO00/17184 Pamphlet), pyrimidone derivatives (see WO00/18758, WO01/70683, WO01/70729, WO01/70728, WO01/70727, WO01/70726, and WO01/70725 Pamphlets), pyrrole-2,5-dione derivatives (see WO00/21927 and WO01/74771 Pamphlets), diamino-1,2,4-triazolecarboxylic acid derivatives (see WO01/09106 Pamphlet), pyrazine derivatives (see WO01/44206 Pamphlet), bicyclic inhibitor (see WO01/44246 Pamphlet), indirubine derivatives (see WO01/37819 Pamphlet), carboxamide derivatives (see WO01/42224 Pamphlet), peptide inhibitors (see WO01/49709 Pamphlet), 2,4-diaminothiazole derivatives (see WO01/56567 Pamphlet), thiadiazolidindione derivatives (see WO01/85685 Pamphlet), aromatic amide derivatives (see WO01/81345 Pamphlet), and so on.

Also, the claims of WO02/085909 Pamphlet show a wide variety of compounds including pyrrolopyrimidine derivatives. However, bicyclic pyrrolopyrimidine derivatives actually synthesized are those having cyano groups at the 7-position of pyrrolopyrimidine ring and limited variety of substituents at other substitutable positions. In addition, while it discloses a method for assaying inhibitory activity of GSK-3 etc., it is silent about which compounds have such activities.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide novel compounds which are specific to and capable of strongly inhibiting the activity of GSK-3 while being clinically applicable, and pharmaceutical compositions as GSK-3 inhibitors using them as effective ingredients.

Also, another object of the present invention is to provide an agent for treating or preventing a GSK-3-mediated disease.

Further, still another object of the present invention is to provide a method for treating a GSK-3-mediated disease.

The present inventors studied the above objects and consequently reached the following inventions.

Namely, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

in the formula (I),

A¹ represents a single bond or represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms that links a nitrogen atom bonded to A¹ with A² on the same or different carbon atom;

A² represents a single bond or represents a group that links A¹ with G¹ in the form of

A¹-C(═O)-G¹,

A¹-C(═O)—O-G¹,

A¹-C(═O)—NR¹⁰¹-G¹,

A¹-C(═S)—NR¹⁰²-G¹,

A¹-C(═NR¹⁰³)-G¹,

A¹-O-G¹,

A¹-OC(═O)-G¹,

A¹-NR¹⁰⁴-G¹,

A¹-NR¹⁰⁵—C(═O)-G¹,

A¹-NR¹⁰⁶—S(═O)₂-G¹,

A¹-NR¹⁰⁷—C(═O)—O-G¹,

A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹,

A¹-NR¹¹⁰C(═S)-G¹,

A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹,

A¹-S-G¹,

A¹—S(═O)-G¹,

A¹-S(═O)₂-G¹,

A¹-S(═O)₂—NR¹¹³-G¹,

A¹-CR¹¹⁴═CH-G¹,

A¹-CR¹¹⁵═CF-G¹,

A¹-CH═CR¹¹⁶-G¹, or

A¹—CF═CR¹¹⁷-G¹;

G¹ represents a single bond or represents a divalent group which is obtainable by removing two hydrogen atoms from any one of an optionally substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon having 6 to 14 carbon atoms, and an optionally substituted heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

A³ represents a single bond or represents an optionally substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms that links G¹ with A⁴ on the same or different carbon atom;

A⁴ represents a single bond or represents a group that links A³ with G² in the form of

A³-C(═O)-G²,

A³-C(═O)—O-G²,

A³-C(═O)—NR¹²¹-G²,

A³-C(═S)—NR¹²²-G²,

A³-C(═NR¹²³)-G²,

A³—O-G²,

A³-O—C(═O)-G²,

A³-NR¹²⁴-G²,

A³—NR¹²⁵-C(═O)-G²,

A³-NR¹²⁶—S(═O)₂-G²,

A³-NR¹²⁷-C(═O)—O-G²,

A³-NR¹²⁸—C(═O)—NR¹²⁹-G²,

A³-NR¹³⁰-C(═S)-G²,

A³—NR¹³¹—C(═S)—NR¹³²-G²,

A³-S-G²,

A³-S(═O)-G²,

A³-S(═O)₂-G²,

A³-S(═O)₂—NR¹³³-G² or

A³-S(═O)₂—O-G²;

G² represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring;

A⁵ represents a single bond or —NR²⁰¹—;

R² represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an optionally substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring;

A⁶ represents a single bond or represents a group that links R³ with a carbon atom of a pyrrole ring to which A⁶ is bonded, in the form of

R³—NR³⁰¹-pyrrole ring,

R³—C(═O)-pyrrole ring,

R³—NR³⁰²—C(═O)-pyrrole ring,

R³—NR³⁰³—C(═S)-pyrrole ring,

R³—NR³⁰⁴—C(═O)—NR³⁰⁵-pyrrole ring,

R³—C(═O)—NR³⁰⁶-pyrrole ring,

R³—NR³⁰⁷—CH═N-pyrrole ring,

R³—C(═O)—O-pyrrole ring,

R³—O—C(═O)-pyrrole ring,

R³—O-pyrrole ring,

R³—S-pyrrole ring,

R³—S(═O)-pyrrole ring,

R³—S(═O)₂-pyrrole ring,

R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring,

R³—C≡C-pyrrole ring, or

R³—S(═O)₂—C≡C-pyrrole ring;

R³ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an optionally substituted saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring;

A⁶-R³ may be a combination wherein A⁶ represents a group that links a carbon atom of a pyrrole ring to which A⁶ is bonded, with R³ in the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring or R³—C≡C-pyrrole ring, and R³ represents a trimethylsilyl group, a formyl group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, or a cyano group;

R¹⁰¹˜R¹¹⁷, R¹²¹˜R¹³³, R²⁰¹ and R³⁰¹˜R³⁰⁹ are each independently a hydrogen atom or an aliphatic hydrocarbon group having 1 to 4 carbon atoms.

However, when both A¹ and A³ represent acyclic alphatic hydrocarbon groups, at least one of A² or G¹ is not a single bond.

In addition, the present invention provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof represented by the formula (I); and a pharmaceutically acceptable carrier.

Further, the present invention provides a GSK-3 inhibitor comprising the compound or a pharmaceutically acceptable salt thereof represented by the formula (I) as an effective ingredient.

Furthermore, the present invention provides an agent for treating or preventing a GSK-3-mediated disease, comprising the compound or a pharmaceutically acceptable salt thereof represented by the formula (I) as an effective ingredient.

Furthermore, the present invention provides a method for treating a GSK-3-mediated disease, comprising a step of injecting the compound or a pharmaceutically acceptable salt thereof represented by the formula (I) in treatment valid amount to a patient.

Note that, in A¹-G² portion in the formula (1), there also exists a case where different combinations consequently represent the same substituent according to the combination of A¹, A², G¹, A³, A⁴, and G², and combinations containing also substituents of them where they may have substituents. However, the scope of the present invention will not become clear due to this.

Note that the corresponding pyrimidine-thione derivative can be derived from the compound represented by the formula (I) of the present invention through the pyrrolopyrimidine derivative represented by the following formula (II).

in formula (I), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and R³ are as defined in the formula (I); and X¹ is a chlorine atom, a bromine atom, an iodine atom, a C₂-C₁₀ acylthio group, a C₂-C₈ alkoxymethylthio group, a C₁-C₈ alkyl group, or a C₁-C₈ arylsulfonyloxy group).

Still further, the present invention is a compound represented by the following formula (Ic) which can be used as the manufacture intermediate of the pyrrolopyrimidinone derivative represented by the formula (I)

in formula (Ic), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are as defined in the formula (I); and Q represents an optionally substituted a C₂-C₁₀ acyl group, an optionally substituted C₂-C₁₀ alkoxymethyl group or an optionally substituted benzyl group.

BEST MODE FOR WORKING THE INVENTION

The “acyclic aliphatic hydrocarbon group” in the present description contains a straight or branched acyclic aliphatic hydrocarbon group. It may be saturated so far as it is the acyclic aliphatic hydrocarbon group as well and may have one or more double bonds or triple bonds in a chemically possible range.

The “alkyl group” in the present description represents a straight or branched saturated acyclic aliphatic hydrocarbon group, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, t-pentyl, or isohexyl.

The “pyridyl group” in the present description contains N-oxide thereof as well.

The term “cycloalkyl group” in the present description means a saturated alicyclic hydrocarbon group, for example cyclopropyl, cyclobutyl, or cyclohexyl.

The term “heterocyclic” in the present description is not particularly limited so far as it can chemically stably exist if it is monocyclic to tricyclic having 1 to 4 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring, but preferably monocyclic or bicyclic having carbon atoms not more than 9 containing 1 to 3, preferably 1 or 2 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring.

In the formula (I), A¹ represents a single bond or represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms that links a nitrogen atom bonded to A¹ with A² on the same or different carbon atoms.

Examples of the acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms in A¹ include divalent groups obtainable by removing two hydrogen atoms from methane, ethane, propane, butane, 2-methylpropane, pentane, 2-methylbutane, 2,2-dimethylpropane, hexane, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane and 2,2,3-trimethylpropane.

Examples of suitable A¹ include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂—)₅—, —(CH₂)₆—, —CH(CH₃)—, —CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)—, —C(CH₃)₂CH₂—, —CH(CH₃)(CH₂)₂—, CH₂CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)CH₂—, —CH(CH₃)CH₂CH(CH₃)—, —CH₂C(CH₃)₂CH₂—, —CH(CH₃)C(CH₃)₂CH₂—, —CH(CH₂CH₃) (CH₂)₂—, —CH₂CH(CH₂CH₃)CH₂—, —CH(CH₂CH₃)CH(CH₃)CH₂—, —CH(CH₃)CH(CH₂CH₃)CH₂—, —CH(CH₂CH₃)CH₂CH(CH₃)—, —CH(CH₃) (CH₂)₃—, —CH₂CH(CH₃) (CH₂)₂—, —CH(CH₃)CH(CH₃) (CH₂)₂—, —CH(CH₃)CH₂CH(CH₃)CH₂—, —CH₂CH(CH₃)CH(CH₃)CH₂—, —CH₂C(CH₃)₂(CH₂)₂—, —CH(CH₃)C(CH₃)₂CH₂—, —CH(CH₂CH₃)(CH₂)₃—, —CH₂CH(CH₂CH₃) (CH₂)₂—, —CH(CH₃) (CH₂)₄—, —CH₂CH(CH₃) (CH₂)₃—, and —(CH₂)₂CH(CH₃) (CH₂)₂—. Examples of preferred A¹ include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH(CH₃)CH₂—CH(CH₃)CH(CH₃)—, —CH(CH₃) (CH₂)₂—CH₂CH(CH₃)CH₂—, and —CH(CH₃)CH(CH₃)CH₂—. More preferred examples of A¹ include —CH₂—, —(CH₂)₂—, and —(CH₂)₃—. As more preferable examples of A¹, —(CH₂)₂— may be mentioned.

In the formula (I), A² represents a single bond or represents a group that links A¹ and G¹ in the form of A¹-C(═O)-G¹, A¹-C(═O)—O-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹—C(═S)—NR¹⁰²-G A¹-C(═NR¹⁰³)-G¹, A¹-O-G¹, A¹-O—C(═O)-G¹, A¹-NR¹⁰⁴-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁶-S(═O)₂-G¹, A¹-NR¹⁰⁷—C(═O)—O-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, A¹-NR¹¹⁰—C(═S)-G¹, A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹, A¹-S-G¹, A¹-S(═O)-G¹, A¹-S(═O)₂-G¹, A¹-S(═O)₂—NR¹¹³-G¹, A¹-CR¹¹⁴═CH-G¹, A¹-CR¹¹⁵═CF-G¹, A¹-CH═CR¹¹⁶-G¹ or A¹-CF═CR¹¹⁷-G¹ (R¹⁰¹˜R¹¹⁷ are independently a hydrogen atom or a acyclic aliphatic hydrocarbon group having 1 to 4 carbon atoms).

When A¹ and G¹ are linked to each other in the form of A¹-C(═O)—NR¹⁰¹-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰¹ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, cyclopropylmethyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-propynyl, 2-butynyl and 3-butynyl group. The C₁-C₄ acyclic aliphatic hydrocarbon group may also be substituted with one or more substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, a methoxy group, an ethoxy group, an oxo group, a cyano group, a carboxyl group, a carbamoyl group, an amino group, a sulfo group, and a phenyl group. Examples of preferred R¹⁰¹ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-C(═S)—NR¹⁰²-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰² include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰² include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-C(═NR¹⁰³)-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰³ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰³ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁴-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁴ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁴ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁵-C(═O)-G¹, examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹⁰⁵ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁵ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁶—S(═O)₂-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁶ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁶ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁷—C(═O)—O-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁷ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁷ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁸—C(═O)NR¹⁰⁹-G¹, examples of such preferred C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁸ and R¹⁰⁹ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁸ and R¹⁰⁹ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹¹⁰—C(═S)-G¹, examples of such preferred C₁-C₄ aliphatic hydrocarbon group of R¹¹⁰ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹⁰ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹¹ and R¹¹² include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹¹ and R¹¹² include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-S(═O)₂—NR¹¹³-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹³ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹³ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹—CR¹¹⁴═CR¹¹⁵-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹⁴ and R¹¹⁵ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹⁴ and R¹¹⁵ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-CF═CR¹¹⁷-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹⁷ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹⁷ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-CF═CR¹¹⁷-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹⁷ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹⁷ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

Examples of preferred A² include groups that link A¹ and G¹ in the form of A¹-C(═O)-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹-O-G¹, A¹-NR¹⁰⁴-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, A¹—NR¹¹⁰—C(═S)-G¹ and A¹-NR¹¹¹—C(═S)NR¹¹²-G¹, especially preferably in the form of A¹-C(═O)-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹-NR¹⁰⁴-G¹, A¹—NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, and A¹-NR¹¹⁰—C(═S)-G¹. Among them, examples of more preferred A² include groups that link A¹ and G¹ in the form of A¹-C(═O)—NR¹⁰¹-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, and A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹. Here, forms of linkage exemplified as preferred and more preferred A² are preferably combined with structures in which A¹ exists in the form of —(CH₂)₂— or —(CH₂)₃— in the formula (I).

In the formula (I), A³ represents a single bond or represents an optionally substituted divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms that links G¹ and A⁴ on the same or different carbon atoms.

Examples of the acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³ include, in addition to the same as those selected as the examples of A¹, —CH═CH—, —C(CH₃)═CH—, —C(CH₃)═C(CH₃)—, —C(CH₂CH₃)═CH—, —C(CH₂CH₃)═C(CH₃)—, —C(CH₂CH₃)═C(CH₂CH₃)—, —C(CH₂CH₂CH₃)═CH—, —C(CH₂CH₂CH₃)═C(CH₃)—, —CH═CHCH₂—, —C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—, —C(CH₃)═C(CH₃)CH₂—, C(CH₃)═CHCH(CH₃)—, —C(CH₃)═C(CH₃)CH(CH₃)—, —C(CH₃)═CHC(CH₃)₂—, —C(CH₂CH₃)═CHCH₂—, —CH═C(CH₂CH₃)CH₂—, —CH═CHCH(CH₂CH₃)—, —C(CH₂CH₃)═C(CH₃)CH₂—, —C(CH₂CH₃)═CHCH(CH₃)—, —C(CH₃)═C(CH₂CH₃)CH₂—, —CH═C(CH₂CH₃)CH(CH₃)—, —CH═CHCH(CH₂CH₃)—, —C(CH₃)═CHCH(CH₂CH₃)—, —CH═C(CH₃)CH(CH₂CH₃)—, —CH═CH(CH₂)₂—, —C(CH₃)═CH(CH₂)₂—, —CH═C(CH₃)(CH₂)₂—, —CH═CHC(CH₃)CH₂—, —C H═CHCH₂CH(CH₃)—, —C(CH₃)═C(CH₃)(CH₂)₂—, —C(CH₃)═CHCH(CH₃)CH₂—, —C(CH₃)═CHCH₂CH(CH₃)—, —CH₂CH═CHCH₂—, —CH(CH₃)CH═CHCH₂—, —CH₂C(CH₃)═CHCH₂—, —CH(CH₃)C(CH₃)═CHCH₂—, —CH(CH₃)CH═CHCH(CH₃)—, —CH(CH₃)CH═C(CH₃)CH₂—, —CH₂C(CH₃)═C(CH₃)CH₂—, —CH(CH₂CH₃)CH═CHCH₂—, and —CH₂C(CH₂CH₃)═CHCH₂—.

Substituents of divalent substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³ include a hydrocarbon group having 1 to 6 carbon atoms, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a phenoxy group, an amino group, or an alkyl amino group having 1 to 6 carbon atoms.

Examples of such preferred A³ include a single bond, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)—, —CH(CH₃) (CH₂)₂—, —CH═CH— and —CH═CHCH₂—. Further, examples of more preferred A³ include a single bond, —CH₂—, —(CH₂)₂— and —(CH₂)₃—. The same applies when A³ is substituted, but a single bond is excluded.

In the formula (I), A⁴ represents a single bond or represents a group that links A³ and G² in the form of A³-C(═O)-G², A³-C(═O)—O-G², A³-C(═O)—NR¹²¹-G², A³-C(═S)—NR¹²²-G², A³-C(═NR¹²³)-G², A³-O-G², A³-O—C(═O)-G², A³-NR¹²⁴-G², A³-NR¹²⁵—C(═O)-G², A³-NR¹²⁶—S(═O)₂-G², A³-NR¹²⁷—C(═O)—O-G², A³-NR¹²⁸—C(═O)—NR¹²⁹-G², A³—NR¹³⁰—C(═S)-G², A³-NR¹³¹—C(═S)—NR¹³²-G², A³-S-G², A³-S(═O)-G², A³-S(═O)₂-G², A³-S(═O)₂—NR¹³³-G² or A³-S(═O)₂—O-G² (in which R¹²¹ through R¹³³ are each independently a hydrogen atom or a acyclic aliphatic hydrocarbon group having 1 to 4 carbon atoms).

When A³ and G² are linked to each other in the form of A³-C(═O)—NR¹²¹-G², examples the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²¹ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²¹ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-C(═S)—NR¹²²-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²² include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²² include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-C(═NR¹²³)-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²³ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²³ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁴-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²⁴ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁴ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁵—C(═O)-G², examples of the C₁-C₄ aliphatic hydrocarbon group of R¹²⁵ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁵ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁶—S(═O)₂-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²⁶ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁶ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁷—C(═O)—O-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²⁷ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁷ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁸—C(═O)—NR¹²⁹-G², examples of the C₁-C₄ aliphatic hydrocarbon group of R¹²⁸ and R¹²⁹ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁸ and R¹²⁹ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹³⁰—C(═S)-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹³⁰ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹³⁰ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹³¹—C(═S)—NR¹³²-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹³¹ and R¹³² include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹³¹ and R¹³² include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-S(═O)₂—NR¹³³-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹³³ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹³³ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

Examples of such A⁴ include a single bond and a group that links A³ and G² in the form of A³-C(═O)-G², A³-C(═O)—O-G², A³—C(═O)—NR¹²¹-G², A³—O-G², A³—NR¹²⁴-G², A³—NR¹²⁵—C(═O)-G², A³-S(═O)₂-G² or A³-S(═O)₂—O-G².

In the formula (I), G¹ represents a single bond or a divalent group obtainable by removing two hydrogen atoms from any of groups consisting of a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and a heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring.

In the formula (I), when G¹ represents a substituted or unsubstituted divalent alicyclic hydrocarbon group having 3 to 10 carbon atoms, examples of the alicyclic hydrocarbon group having 3 to 10 carbon atoms include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, bicyclo[2.2.1]heptane, bicyclo[2.2. 1]heptene, bicyclo[3.1.1]heptane and bicyclo[2.2. 2]octane. Examples of such preferred C₃-C₁₀ alicyclic hydrocarbon of G¹ include monocyclic alicyclic hydrocarbon group having 3 to 6 carbon atoms such as cyclopropane, cyclopentane, cyclohexane and the like.

Examples of the substituent for the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G¹ include: a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, isohexyloxy, 2-methyl-pentyloxy, 1-ethylbutoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclopentylmethyloxy and cyclohexylmethyloxy or another C₁-C₇ alkoxy group consisting of a straight or branched alkyl, cycloalkyl and oxy group, ethylene dioxy or another C₁-C₄ alkylenedioxy group, phenoxy, 1-naphthoxy and 2-naphthoxy or another C₆-C₁₀ aryloxy group, benzyloxy, α-phenethyloxy, β-phenethyloxy and phenylpropyloxy or another C₇-C₉ aralkoxy group, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy or another C₂-C₇ acyloxy group, oxo, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, butylsulfonyloxy and t-butylsulfonyloxy or another C₁-C₆ alkylsulfonyloxy group consisting of a straight or branched alkyl and sulfonyloxy, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaroyl and hexanoyl or another C₂-C₇ acyl group, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl or another C₂-C₇ alkoxycarbonyl group consisting of a straight or branched alkyl and oxycarbonyl group, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N-cyclopropylcarbamoyl, N-cyclobutylcarbamoyl, N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl, N-cycloheptylcarbamoyl, N-cyclopropylmethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl and N,N-dipropylcarbamoyl or another C₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkyl, cycloalkyl and carbamoyl group, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutyl-amino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino or another C₁-C₆ alkylamino group consisting of a straight or branched alkyl, cycloalkyl and amino group, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino or another C₂-C₇ acylamino group, methoxycarbonylamino, ethoxycarbonylamino and t-butoxycarbonylamino or another C₂-C₈ alkoxycarbonylamino group, methylsulfonylamino, ethylsulfonylamino, butylsulfonylamino and t-butylsulfonylamino or another C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio or another C₁-C₆ alkylthio group, methylsulfynyl, ethylsulfynyl, propylsulfynyl, isopropylsulfynyl, butylsulfynyl, isobutylsulfynyl, s-butylsulfynyl, t-butylsulfynyl, pentylsulfynyl and cyclopentylsulfynyl or another C₁-C₆ alkylsulfynyl group consisting of a straight or branched alkyl, cycloalkyl and sulfynyl group, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butyl-sulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl or another C₁-C₆ alkylsulfonyl group consisting of a straight or branched alkyl, cycloalkyl and sulfonyl group, a sulfo group, a sulfamoyl group, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutylamino-sulfonyl, s-butylaminosulfonyl, pentylaminosulfonyl, dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, cyclopropyl-aminosulfonyl, cyclopentylaminosulfonyl, cyclohexylamino-sulfonyl and cyclopropylmethylaminosulfonyl or another C₁-C₆ aminosulfonyl group consisting of a straight or branched alkyl, a cycloalkyl and aminosulfonyl group, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or another alicyclic hydrocarbon group having 3 to 6 carbon atoms, methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl or another aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain a straight or branched unsaturated bond.

As the substituent of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms as G¹, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms or an aliphatic hydrocarbon group having 1 to 6 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a C₂-C₇ acyl group such as methoxymethyloxy group, 2-methoxyethoxy group, formyl group, trifluoroacetyl group, acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbambyl, N-cyclopropylcarbamoyl or N-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methyl-propylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a C₁-C₇ acylamino group such as trifluoroacetylamino group, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; and a cyano group).

In the formula (I), when G¹ represents a substituted or unsubstituted divalent aromatic hydrocarbon group having 6 to 14 carbon atoms, examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms include a compound having at least one aromatic ring on its molecule, such as benzene, indene, indane, naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, azulene, acenaphthylene, acenaphthene, fluorene, phenanthrene or anthracene.

Examples of such preferred aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹ include benzene, naphthalene and indane. Examples of more preferred aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹ include benzene.

Exemplary substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹ include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇-acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms and an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms.

Specific examples of the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹ include the same as those specifically exemplified as the substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G¹.

As the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, the C₁-C₇ alkoxy group, the C₂-C₇ acyl group, the C₂-C₇ alkylcarbamoyl group, the C₁-C₆ alkylamino group, the C₂-C₇ acylamino group, the alicyclic hydrocarbon group having 3 to 6 carbon atoms or the aliphatic hydrocarbon group having 1 to 6 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; and a cyano group).

Preferred examples of the substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G₁ include a fluorine atom; a chlorine atom; a bromine atom; a C₁-C₆ alkoxy group consisting of a straight or branched alkyl and oxy group, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy; a cyano group; a nitro group; a carboxyl group; a hydroxy group; an amino group; a C₁-C₆ mono or dialkylamino group consisting of a straight or branched alkyl and amino group, including methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutyl-amino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino; a carbamoyl group; an aminosulfonyl group; an alicyclic hydrocarbon group having 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a C₂-C₇ acyl group including acetyl, propionyl, butyryl, isobutyryl, pivaroyl and hexanoyl; a C₁-C₆ alkylthio group including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; a C₁-C₆ alkylsulfonyl group including methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl and hexylsulfonyl; a C₂-C₇ alkoxycarbonyl group including acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy; a C₂-C₇ acylamino group including acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; trifluoromethyl group, trifluoromethoxy group, and an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain a straight or branched unsaturated bond, including methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl.

Specifically, examples of more preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms include a fluorine atom, a chlorine atom, a bromine atom, C₁-C₆ alkoxy group, cyano group, a nitro group, a carboxyl group, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylamino group, a carbamoyl group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, a C₁-C₆ alkylsulfonyl group, a C₂-C₇ alkoxycarboxyl group, trifluoromethyl group, trifluoromethoxy group, and a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl. Examples of particularly preferred substituents include a fluorine atom, a chlorine atom, a C₁-C₆ alkoxy group, a cyano group, a nitro group, a carboxyl group, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, a trifluoromethyl group, a trifluoromethoxy group and a C₁-C₆ alkyl group.

In the formula (I), when G¹ represents a divalent group derived from heterocyclic compounds having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring, examples of such heterocyclic compounds include monocyclic, bicyclic or tricyclic heterocyclic compounds, such as furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, furazan, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, 1,4-dioxacycloheptane, benzothiophene, indole, 1,2-methylene-dioxybenzene, benzimidazole, benzothiazole, benzooxazole, chroman, isochroman, quinoline, decahydrbquinoline, isoquinoline, phthalazine, cinnoline, 1,8-naphthylidine, 1,2,3,4-tetrahydroisoquinoline, quinazoline, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine, pyrrolopyrimidine, pyrazolpyrimidine or quinuclidine.

Preferred examples of the heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G¹ include monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compounds having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as furan, pyrrole, thiophene, pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran, 1,2-methylenedioxybenzene, benzimidazole, indole, quinoline, isoquinoline, quinazoline, phthalazine, cinnoline or 1,8-naphthylidin; or monocyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine.

The heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G¹ links to A² on a carbon atom or a nitrogen atom.

More preferred examples of the heterocyclic group linking to A² on a carbon atom include divalent groups derived from monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compounds having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as furan, pyrrole, thiophene, pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine; pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran, 1,2-methylenedioxybenzene, benzimidazole, indole, quinoline, isoquinoline or quinazoline.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, the heterocyclic group linking to A² on a nitrogen atom, include divalent groups derived from monocyclic or bicyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine. More preferred examples of the monocyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, include piperidine, homopiperidine, morpholine, homopiperazine and piperazine.

Exemplary substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹, include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, and an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms.

Specific examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹ include the same as those exemplified in the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G¹.

As the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms and aliphatic hydrocarbon group having 1 to 6 carbon atoms may further be substituted with (one or more substituents selected from the group consisting of a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropyl-carbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; and a cyano group).

Preferred examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹, include a fluorine atom; a chlorine atom; a bromine atom; a C₁-C₆ alkoxy group consisting of a straight or branched alkyl and oxy group, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy; a cyano group; a nitro group; a carboxyl group; a hydroxy group; an amino group; a C₁-C₆ mono or dialkylamino group consisting of a straight or branched alkyl and amino group, including methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino; a carbamoyl group; an aminosulfonyl group; an alicyclic hydrocarbon group having 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a C₂-C₇ acyl group including acetyl, propionyl butyryl, isobutyryl, pivaroyl and hexanoyl; a C₁-C₆ alkylthio group including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; a C₁-C₆ alkylsulfonyl group, including methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl and hexylsulfonyl; a C₂-C₇ alkoxycarbonyl group including acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy; a C₂-C₇ acylamino group including acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; trifluoromethyl, trifluoromethoxy, and an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain a straight or branched unsaturated bond, including methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl.

Specifically, more preferred examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹, include a fluorine atom, a chlorine atom, a bromine atom, C₁-C₆ alkoxy group, cyano group, a nitro group, a carboxyl group, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylamino group, a carbamoyl group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, a C₁-C₆ alkylsulfonyl group, a C₂-C₇ alkoxycarboxyl group, a trifluoromethyl group, a trifluoromethoxy group, and a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl. Examples of particularly preferred substituents include a fluorine atom, a chlorine atom, a C₁-C₆ alkoxy group, a cyano group, a nitro group, a carboxyl group, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, a trifluoromethyl group, a trifluoromethoxy group and a C₁-C₆ alkyl group.

In the present invention, G¹ in the formula (I) is preferably a single bond, a monocyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, a phenylene group, a monocyclic or bicyclic aromatic hydrocarbon group having 3 to 9 carbon atoms having 1 or 2 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring, or a monocyclic heterocyclic group having 2 to 9 carbon atoms having 1 or 2 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring.

In the formula (I), G² represents a hydrogen atom, a substituted or unsubstituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or a substituted or unsubstituted heterocyclic group having 1 to 4 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring.

In formula (I), when G² represents a substituted or unsubstituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, examples of such a acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G² include an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl, hexyl, heptyl, 2-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 6-methylheptyl, octyl, nonyl or decyl, an alkenyl group such as vinyl, 1-methylvinyl, 1-ethylvinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 2-methyl-1-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,5-hexadienyl, 2-heptenyl, 2-octenyl, 2-nonenyl or 2-decenyl, or an alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-3-pentynyl, 1-methyl-3-hexynyl, 2-heptynyl, 2-octynyl, 2-nonynyl or 2-decynyl.

Specifically, more preferred examples of such aliphatic hydrocarbon group having 1 to 10 carbon atoms include a straight or branched C₁-C₆ alkyl group which may contain a unsaturated bond such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, vinyl, 1-prophenyl, 1-butenyl, ethynyl or 1-propynyl. Particularly preferred examples of such a acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms include a straight or branched C₁-C₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl or hexyl.

Exemplary substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G² include: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₇ alkoxy group consisting of a straight or branched alkyl group, cycloalkyl group and oxy group, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, isohexyloxy, 2-methylpentyloxy, 1-ethylbutoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclopentyl methyloxy and cyclohexylmethyloxy; an alkyldioxy group having 1 to 4 carbon atoms such as ethylene dioxy; a C₆-C₁₀ aryloxy group, including phenoxy, 1-naphthoxy and 2-naphthoxy; a C₇-C₉ aralkoxy group, including benzyloxy, α-phenethyloxy, β-phenethyloxy and phenylpropyloxy; a C₂-C₇ acyloxy group including acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy; an oxo group; a C₁-C₆ alkylsulfonyloxy group consisting of a straight or branched alkyl and sulfonyloxy, including oxo, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, butylsulfonyloxy and t-butylsulfonyloxy; a C₂-C₇ acyl group, including acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaroyl and hexanoyl; a carboxyl group; a C₂-C₇ alkoxycarbonyl group consisting of a straight or branched alkyl and oxycarbonyl group, including methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkyl, cycloalkyl and carbamoyl group, including N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N-cyclopropylcarbamoyl, N-cyclobutylcarbamoyl, N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl, N-cycloheptylcarbamoyl, N-cyclopropylmethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl and N,N-dipropylcarbamoyl; an amino group; a C₁-C₆ alkylamino group consisting of a straight or branched alkyl, cycloalkyl and amino group, including methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino, N-methylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino; a C₂-C₇ acylamino group including acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; a C₂-C₈ alkoxycarbonylamino group, including methoxycarbonylamino, ethoxycarbonylamino and t-butoxy-carbonylamino; a C₁-C₆ alkylsulfonylamino group including methylsulfonylamino, ethylsulfonylamino, butylsulfonylamino and t-butylsulfonylamino; a cyano group; a nitro group; a C₁-C₆ alkylthio group including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; a C₁-C₆ alkylsulfynyl group consisting of a straight or branched alkyl, cycloalkyl and sulfynyl group, including methylsulfynyl, ethylsulfynyl, propylsulfynyl, isopropylsulfynyl, butylsulfynyl, isobutylsulfynyl, s-butylsulfynyl, t-butylsulfynyl, pentylsulfynyl and cyclopentylsulfynyl; a C₁-C₆ alkylsulfonyl group consisting of a straight or branched alkyl, cycloalkyl and sulfonyl group, including methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl; a sulfo group; a sulfamoyl group; a C₁-C₆ aminosulfonyl group consisting of a straight or branched alkyl, cycloalkyl and aminosulfonyl group, including methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutyl-aminosulfonyl, s-butylaminosulfonyl, pentylaminosulfonyl, dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, cyclopropylaminosulfonyl, cyclopentylaminosulfonyl, cyclohexylaminosulfonyl and cyclopropylmethylaminosulfonyl; an alicyclic hydrocarbon group having 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain a straight or branched unsaturated bond, including methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl; an aromatic hydrocarbon group having 6 to 14 carbon atoms which is a monovalent group derived from monocyclic, bicyclic or tricyclic aromatic hydrocarbon group, including benzene, naphthalene, indene, indane, 1,2,3,4-tetrahydronaphthalene, and fluorene; and a monovalent group derived from monocyclic, bicyclic or tricyclic heterocyclic compound, including furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, benzimidazole, benzothiazole, benzooxazole, chroman, isochroman, quinoline, decahydroquinoline, isoquinoline, quinazolin, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine and quinuclidine, the heterocyclic compound (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Preferred examples of the substituent of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² include a fluorine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, an oxo group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

More preferred exemplary substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² include a fluorine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a carboxyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, a cyano group, a benzyl group, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

As the substituent of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G², the heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), links to the aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² on a carbon atom or a nitrogen atom.

Preferred examples of the heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), links to the aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² on a carbon atom, include a monovalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound, including furan, pyrrole, thiophene, pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran, 1,2-methylenedioxybenzene, benzimidazole, indole, quinoline, isoquinoline and quinazolin, the monovalent group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

Meanwhile, preferred examples of the heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), links to the acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² on a nitrogen atom, include a monovalent group derived from a monocyclic C₂-C₉ heterocyclic compound, including pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine and piperazine, the monovalent group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

As the substituent of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, C₂-C₇ alkylcarbamoyl, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, aromatic hydrocarbon group having 6 to 14 carbon atoms, and heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, examples of the alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl group. Preferred examples of the alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-cyclopentenyl, 4-cyclopentenyl, 1-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cycloheptenyl.

Exemplary substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, C₁-C₄ alkylenedioxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, and an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms.

Specific examples of the substituent of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² include the same as those exemplified in the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an aromatic hydrocarbon group having 6 to 14 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino, a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms include a monovalent group having at least one aromatic ring on its molecule, such as benzene, indene, indane, naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, azulene, acenaphthylene, acenaphthene, fluorene, phenanthrene or anthracene. Examples of such preferred aromatic hydrocarbon group having 6 to 14 carbon atoms of G² include a phenyl group.

Exemplary substituents of the aromatic hydrocarbon group having 6 to 14 carbon atoms of G² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₁-C₄ alkylenedioxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms.

Specific examples of the substituent of the substituted C₆-C₁₄ aromatic hydrocarbon group of G² include the same as those exemplified in the substituent of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituents of the aromatic hydrocarbon group having 6 to 14 carbon atoms of G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an aromatic hydrocarbon group having 6 to 14 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring, examples of such heterocyclic group include a monovalent group derived from monocyclic, bicyclic or tricyclic compounds, including furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, 1,2-methylene-dioxybenzene, benzimidazole, benzothiazole, benzooxazole, chroman, isochroman, quinoline, decahydroquinoline, isoquinoline, quinazolin, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine and quinuclidine.

Preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G² include 2-pyridyl, 3-pyridyl, 4-pyridyl, piperidino, 2-piperizyl, 3-piperizyl, 4-piperizyl, morpholino, 1-homopiperidinyl, 1-pyrrolidinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 4-isooxazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 4-triazolyl, 5-tetrazolyl, 1-piperazinyl, 4-tetrahydropyranyl, 2-1,3,4-oxadiazolyl, 4-1,2,3-thiadiazolyl, 2-benzofuranyl, 2-benzothiazolyl, 2-indolyl, 3-indolyl, 5-benzoimidazolyl and 2-1,2,3,4-tetrahydroisoquinolinyl group.

The heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G², links to A⁴ on a carbon atom or a nitrogen atom.

More preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G², the heterocyclic group linking to A⁴ on a carbon atom, include a monovalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as furan, pyrrole, thiophene, pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran, 1,2-methylenedioxy-benzene, benzimidazole, indole, quinoline, isoquinoline or quinazolin.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G², the heterocyclic group linking to A⁴ on a nitrogen atom, include a monovalent group derived from a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine.

More preferred examples of the heterocyclic group as G² include a monovalent group derived from a monocyclic C₄-C₆ heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as piperidine, homopiperidine, morpholine, homopiperazine, or piperazine.

Exemplary substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₁-C₄ alkylenedioxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and.

The substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G² are as defined above for the substituent of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an aromatic hydrocarbon group having 6 to 14 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropyl-carbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the present description, when G¹, G², or the substituent of G² represents a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted alicyclic hydrocarbon group, or a substituted or unsubstituted heterocyclic group, the aromatic hydrocarbon group, alicyclic hydrocarbon group, or heterocyclic group is preferably selected from the group consisting of cyclopropane, cyclopentane, cyclohexane, cyclohexene, cycloheptane, *nolvolnane, adamantine, benzene, naphthalene, indane, indoles, 1,3-benzodioxol, benzoimidazol, benzotriazol, pyrazol, imidazol, pyrazoron, thiazol, tetrazol, 1,2,4-oxadiazol, isooxazol, furan, thiophene, pyridine, pyradine, pyrrole, morpholine, benzofuran, benzothiophene, piperazine, pyrrolidine, homopiperizine, tetrahydroisoquinoline, pyrimidine, and quinazoline.

Next, an explanation will be given of preferred combinations of A¹, A², G¹, A³, A⁴ and G² in the formula (I).

When both of A¹ and A³ represent aliphatic hydrocarbon group, at least one of A² and G¹ is not a single bond.

The preferred combinations of A¹, A², G¹, A³, A⁴ and G², and preferred combinations including also substituents of them if they have substituents are basically preferably combinations of those preferably selected from among A¹, A², G¹, A³, A⁴ and G², and substituents of them. Then, more preferred combinations are combinations of more preferred elements.

In the formula (I), A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, particularly preferably represents —(CH₂)₂— or —(CH₂)₃—.

More preferably, A² simultaneously represents those other than the single bond, and especially preferably A² represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—. Specifically preferably A² represents —C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

Meanwhile, where A¹ represents a single bond, preferably also A represents a single bond.

Preferred combinations of G¹, A³, A⁴ and G² of G¹-G² portion include combinations of 1 to 10 of the following table. Combi- nation G¹ A³ A⁴ G² 1 Group other Single bond Single bond Hydrogen than single atom bond 2 Single bond Group other than Single bond Hydrogen single bond atom 3 Group other Single bond Single bond Group other than single than a bond hydrogen atom 4 Single bond Group other than Single bond Group other single bond than a hydrogen atom 5 Group other Single bond Group other Group other than single than single than a bond bond hydrogen atom 6 Single bond Group other than Group other Group other single bond than single than a bond hydrogen atom 7 Group other Group other than Single bond Group other than single single bond than a bond hydrogen atom 8 Group other Group other than Group other Group other than single single bond than single than a bond bond hydrogen atom 9 Group other Group other than Group other Hydrogen than single single bond than single atom bond bond 10 Single bond Single bond Single bond Hydrogen atom

In the table, in combinations of numbers 4 to 7, A³ represents an alkylene group having 1 to 3 carbon atoms.

Also, in the combination of number 5, A⁴ preferably represents —C(═O)—, —C(═O)—NH—, —O—, or —NH—C(═O)—.

Also, in the combination of number 8, A⁴ preferably represents —O—.

Further, combinations of the following a) to f) are preferable.

a) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)— or —NH—(C═O)—NH—, G¹ represents a single bond, and A³ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms.

b) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)—, —NH—(C═O)—NH—, —NH—, or —C—(═O)—NH—, and G¹ represents a group other than the single bond.

c) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents a single bond, and G¹ represents an optionally substituted heterocyclic group (note, where a heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, the 5 or 6 membered monocyclic heterocyclic group of G¹ is substituted, or A³-G² portion represents those other than the hydrogen atom).

d) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, and G¹ represents an optionally substituted aromatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group having 7 to 10 carbon atoms, or an optionally substituted heterocyclic group (note, where the aromatic hydrocarbon group of G¹ is a phenyl group, or where the heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, the phenyl group or 5 or 6 membered monocyclic heterocyclic group of G¹ is substituted, or A³-G² portion represents those other than the hydrogen atom).

e) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, G¹ and A⁴ represent the single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, G² represents an optionally substituted alicyclic hydrocarbon group having 5 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group, or optionally substituted heterocyclic group.

f) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, G¹ represents the single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, and A⁴ represents —C(═O)—, —C(═O)—NR¹²¹—, —C(═S)—NR¹²²—, —C(═NR¹²³), —O—C(═O)—, —NR¹²⁵—C(═O)—, —NR¹²⁶—S(═O)₂—, —NR¹²⁷—C(═O)—O—, —NR¹²⁸—C(═O)—NR¹²⁹—, —NR¹³⁰—C(═S)—, —NR¹³¹—C(═S)—NR¹³²—, —S—, —S(═O)—, —S(═O)₂—, —S(═O)₂—NR¹³³— or —S(═O)₂—O—.

In the cases of d) to f), A² preferably represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—, especially preferably represents —C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

In the formula (I), A⁵ represents a single bond or represents a group that links R² with a carbon atom of a pyrrole ring to which A⁵ is bonded, in the form of R²—NR²⁰¹-pyrrole ring (R²⁰¹ represents a hydrogen atom or a acyclic aliphatic hydrocarbon group having 1 to 4 carbon atoms), when A⁵ bonds R² and a carbon atom of a pyrrole ring to which A⁵ is bonded, in the form of R²—NR²⁰¹-pyrrole ring, examples of the acyclic aliphatic hydrocarbon group having 1 to 4 carbon atoms of R²⁰¹ are the same as those exemplified as R¹⁰¹ of A² described above. Preferred examples of R¹⁰² include a hydrogen atom, methyl, ethyl or propyl group, and specifically preferably hydrogen atom and methyl group.

Preferred examples of A⁵ include a single bond, —NH—, and N(CH₃)—, and specifically preferably single bond.

In the formula (I), R² represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

R² in the formula (I) is preferably a chlorine atom or a bromine atom among a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the formula (I), when R² represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, examples of acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R² are the same as those exemplified of the acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G². Preferred examples of the acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R² include methyl, ethyl, isopropyl, butyl, isobutyl, t-butyl, t-pentyl, vinyl, 2-propenyl, 2-methyl-1-propenyl, and 2-propenyl.

Substituents for the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R² include the same as those exemplified as the substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇-acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, aromatic hydrocarbon group having 6 to 14 carbon atoms, and heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R² represents a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² the same as defined above for the substituents of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of G². Preferred examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Among them, the cyclopropyl group is preferred.

Exemplary substituents of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include the same as those exemplified in the substituted alicyclic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino, N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group, and a trifluoromethoxy group).

In the formula (I), when R² is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms of R² include the same as those exemplified in the aromatic hydrocarbon group having 6 to 14 carbon atoms of G². Examples of such preferred aromatic hydrocarbon group having 6 to 14 carbon atoms of R² include a phenyl group.

Exemplary substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, a C₁-C₆ alkyl group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms R² include the same as those exemplified for the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the aromatic hydrocarbon group having 6 to 14 carbon atoms of R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms and heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group, a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group, and a trifluoromethoxy group).

In the formula (I), when R² represents a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring of R², examples of heterocyclic group of R² include the same as those exemplified for the heterocyclic group of G² The heterocyclic group of R² links to A⁵ on a carbon atom or a nitrogen atom.

Examples of preferred heterocyclic group linking to A⁵ on a carbon atom include a monocyclic or cyclic C₃-C₉ aromatic heterocyclic group having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, benzothienyl, quinolyl, isoquinolyl, quinazolyl, benzoimidazolyl or benzooxazolyl. More preferred example of the heterocyclic group include a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 2-furyl, 2-thienyl, 2-pyrrolyl, 2-imidazolyl, 5-imidazolyl, 4-pyrazolyl, 2-oxazolyl, 5-oxazolyl, 5-isooxazolyl, 2-thiazolyl, 5-thiazolyl, 5-isothiazolyl, 3-isothiazolyl, 2-pyridyl, 2-pyrimidinyl, 2-benzofuranyl or 2-benzothiophenyl group. Further, particularly preferable examples of the heterocyclic group include a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, and most preferably, 2-furyl, 2-thienyl, 2-pyrrolyl, 2-pyridyl or 4-pyrazolyl.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, links to A⁵ on a nitrogen atom, include 1-pyrazolyl, 1-imidazolyl, 1-pyrrolidinyl, piperidino, morpholino, 1-homopiperidinyl and 1-piperazinyl. When the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on a ring of R², links to A⁵ on a nitrogen atom, A⁵ represents a single bond.

Exemplary substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted ring of R² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R² include the same as those exemplified as the substituents of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring) may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isbbutyrylamino or valerylamino; a C₁-C₆-alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

Among exemplary substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R², preferred examples of the substituent include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, a cyano group, a nitro group, an amino group, a C₁-C₆ mono or dialkylamino group consisting of a straight or branched alkyl group and an amino group, such as substituted or unsubstituted methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino, a carboxyl group, an optionally substituted saturated a C₁-C₆ alkyl group including a substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl, an alicyclic hydrocarbon group having 3 to 6 carbon atoms including cyclopropyl, cyclobutyl, cyclo pentyl and cyclohexyl, an optionally substituted C₁-C₆ alkoxy group consisting of a straight or branched alkyl group and an oxy group, including a substituted or unsubstituted methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy, a C₂-C₇ acyl group, including a substituted or unsubstituted acetyl, propionyl, butyryl, isobutyryl, pivaroyl and hexanoyl, a C₁-C₆ alkylthio group, including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio, trifluoromethyl group, trifluoromethoxy group, a C₂-C₇ acylamino group, including substituted or unsubstituted acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino, and a C₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkyl group and a carbamoyl group, including a substituted or unsubstituted N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl.

More preferred examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring as R², include one or more of a fluorine atom, a chlorine atom, a bromine atom, an acyl group having 2 to 4 carbon atoms, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a substituted or unsubstituted C₁-C₆ alkyl group, a hydroxy group, and a substituted or unsubstituted C₁-C₆ alkoxy group.

Here, an explanation will be given of preferred combinations of R² and A⁵ of the formula (I).

In combinations of R² and A⁵ of the formula (I) in the present invention, when R² is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, A⁵ represents a single bond.

Preferred examples of the combinations of R² and A⁵ of the formula (I) in the present invention include those representing an aliphatic hydrocarbon group having 1 to 10 carbon atoms wherein A⁵ represents a single bond, and R² may be substituted, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group. Specific preferred combinations are combinations representing an aliphatic hydrocarbon group having 1 to 10 carbon atoms wherein A⁵ represents a single bond, and R² may be substituted, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted phenyl group, or an optionally substituted heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. Among them, cases where R² represents a cyclopropyl group, a cyclobutyl group, a cyclopropylmethyl group, a methyl group, an ethyl group, a vinyl group, an isopropyl group, an isobutyl group or 2-methyl-1-propenyl group are preferred.

Also, combinations of A⁵ and R² in which A⁵ represents a single bond and R² represents a thienyl group, a pyridyl group, a furyl group, a pyrazolyl group or a phenyl group are preferable, wherein the thienyl group, the pyridyl group, the furyl group, the pyrazolyl group or the phenyl group may be further substituted by one or more of a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, a C₂-C₄ acyl group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a fluorine atom or a chlorine atom.

Also a combination wherein A⁵ is NR²⁰¹-, and R² represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms is preferred.

In the formula (I), A⁶ is a single bond, a group that links a carbon atom of a pyrrole ring in which R³ and A⁶ are linked to each other in the form of R³—NR³⁰¹-pyrrole ring, R³—C(═O)-pyrrole ring, R³—NR³⁰²—C(═O)-pyrrole ring, R³—NR³⁰³—C(═S)-pyrrole ring, R³—NR³⁰⁴—C(═O)—NR³⁰⁵-pyrrole ring, R³—C(═O)—NR³⁰⁶-pyrrole ring, R³—NR³⁰⁷—CH═N-pyrrole ring, R³—O—C(═O)-pyrrole ring, R³—C(═O)—O-pyrrole ring, R³—O-pyrrole ring, R³—S-pyrrole ring, R³—S(═O)-pyrrole ring, R³—S(═O)₂-pyrrole ring, R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring, R³—C≡C-pyrrole ring, or R³—S(═O)₂—C≡C-pyrrole ring (R³⁰¹ through R³⁰⁹ are each independently a hydrogen atom or a C₁-C₄ aliphatic hydrocarbon group.)

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰¹-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰¹ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰¹ include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰²—C(═O)-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰² include the same as those selected as the examples of R¹ in A². Examples of such preferred R³⁰² include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰³—C(═S)-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰³ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰³ include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰⁴——C(═O)—NR³⁰⁵-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰⁴ and R³⁰⁵ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰⁴ and R³⁰⁵ include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—C(═O)—NR³⁰⁶-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰⁶ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰⁶ include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰⁷—CH═N-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰⁷ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰⁷ include a hydrogen atom, methyl, and ethyl group. Particularly, methyl group is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰⁸ and R³⁰⁸ include the same as those selected as the examples of R¹⁰¹ in A².

In the formula (I), R³ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a substituted or unsubstituted saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.

As R³ in the formula (I), among a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, a chlorine atom, a bromine atom, and an iodine atom are preferred.

In the formula (I), when R³ represents a substituted or unsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, examples of the acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³ include an alkyl group, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl, hexyl, heptyl, 2-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 6-methylheptyl, octyl, nonyl, and decyl. Preferred examples of the acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³ include methyl, ethyl, isopropyl, butyl, t-butyl, and t-pentyl group.

As the substituent of the substituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³ include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³ include the same as those exemplified in the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino, N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino, a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include the same as those exemplified in the alicyclic hydrocarbon group having 3 to 10 carbon atoms of G². Preferred examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include cyclopropyl, cyclobutyl and cyclopentyl, cyclohexyl.

Exemplary substituents of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R³ include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a cyano group, a nitro group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R³ include the same as those exemplified as the substituents of the substituted the substituents of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ Cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms of R³ include the same as those exemplified in the aromatic hydrocarbon group having 6 to 14 carbon atoms of G². Preferred examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms of R³ include a phenyl group.

Exemplary substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of R³ include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of R³ include the same as those exemplified in the substituent of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino, N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring, examples of such heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ include the same as those exemplified in the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of G².

The heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ links to A⁶ on a carbon atom or a nitrogen atom.

Preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ and linking to A⁶ on a carbon atom, include a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic group having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, including furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, N-oxopyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, benzothienyl, quinolyl, isoquinolyl, quinazolyl, benzoimidazolyl and benzooxazolyl, preferably 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 2-oxazolyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-N-oxopyridyl, 3-N-oxopyridyl, 4-N-oxopyridyl, 3-pyrazolyl, 4-pyrazolyl, 4-imidazolyl, 2-pyrimidinyl, or 5-pyrimidinyl.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ and linking to A⁶ on a nitrogen atom, include 1-imidazolyl, 1-pyrazolyl, 1-pyrrolyl, 1-pyrrolidinyl, piperidino, morpholino, 1-homopiperidinyl and 1-piperazinyl, preferably 1-imidazolyl.

When the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ links to A⁶ on a nitrogen atom, A⁶ is a single bond, or a group that links a carbon atom of a pyrrole ring in which R³ and A⁶ are linked to each other in the form of R³—C(═O)-pyrrole ring.

Exemplary substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R³ include the same as those exemplified in the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms and an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of oxygen atom, a nitrogen atom and a sulfur atom in the ring) may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆-alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

Among those exemplified as substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³, preferred examples thereof include: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a cyano group; a nitro group; an amino group; a C₁-C₆ mono or dialkylamino group consisting of a straight or branched alkyl group and an amino group, including a substituted or unsubstituted methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino; a carboxyl group; a saturated a C₁-C₆ alkyl group including a substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl; an alicyclic hydrocarbon group having 3 to 6 carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a C₁-C₆ alkoxy group consisting of a straight or branched alkyl group and an oxy group, including a substituted or unsubstituted methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy; a C₂-C₇ acyl group including a substituted or unsubstituted acetyl, propionyl, butyryl, isobutyryl, pivaroyl and hexanoyl; a C₁-C₆ alkylthio group, including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; a trifluoromethyl group; a trifluoromethoxy group; a C₂-C₇ acylamino group including a substituted or unsubstituted acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; and a C₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkyl group and a carbamoyl group including a substituted or unsubstituted N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl.

More preferred substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³, include a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted C₁-C₆ alkyl group, a hydroxy group, and a substituted or unsubstituted C₁-C₆ alkoxy group. Specifically, a methyl group and an ethyl group are preferred.

In the formula (I), A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring or R³—C≡C-pyrrole ring. R³ represents a trimethylsilyl group, a formyl group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group or a cyano group, preferred examples thereof include a formyl group, an acetyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group and a cyano group.

Here, an explanation will be given of preferred combinations of R³ and A⁶ in the formula (I).

As combinations of R³ and A⁶ of the formula (I) in the present invention, when R³ represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, A³ represents a single bond.

Also, when R³ represents a trimethylsilyl group, a formyl group, an optionally substituted a C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, or a cyano group, A is a group that links a carbon atom of a pyrrole ring in which R³ and A⁶ are linked to each other in the form of a carbon atom of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring or R³—C≡C-pyrrole carbon atom.

Preferred combinations of R³ and A⁶ of the formula (I) in the present invention include cases where A⁶ represents a single bond and R³ represents an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms or an optionally substituted heterocyclic group. Among them, a case where R³ represents a thienyl group, a furyl group, a pyrrolyl group, a pyrazolyl group or a phenyl group optionally substituted with one or more alkyl group having 1 to 4 carbon atoms is preferred.

Also a case where A⁶ represents a single bond, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group optionally substituted by an alkyl group having 1 to 4 carbon atoms or one halogen atom.

In addition, the following combinations can be mentioned: a combination in which A⁶ represents a single bond, and R³ is a fluorine atom, chlorine atom, bromine atom, or iodine atom, a combination in which A⁶ represents a single bond, and R³ is a substituted or unsubstituted saturated acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ represents a single bond, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ represents a single bond, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ represents a single bond, and R³ is a substituted or unsubstituted monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH—C(═O)-pyrrole ring, and R³ is a hydrogen atom; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C(═O)—NH-pyrrole ring, and R³ is a substituted or unsubstituted acyclic acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of the carbon atom of a R³—C(═O)—NH-pyrrole ring, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C(═O)—NH-pyrrole ring, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of the R³—C(═O)—NH-pyrrole ring, and R³ is a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is a hydrogen atom; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is a substituted or unsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of R³—NH-pyrrole ring, and R³ is a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a hydrogen atom; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked to each other in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a substituted or unsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ is a group that links a carbon atom of a pyrrole ring in which R³ and A⁶ are linked to each other in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a monocyclic C₃-C₅-aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a hydrogen atom; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a substituted or unsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring; and a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a trimethylsilyl group or cyano group.

Here, an explanation will be given of preferred combinations of R²-A⁵ portion and R³-A⁶ portion in the formula (I).

Preferred combinations of R²-A⁵ portion and R³-A⁶ portion include cases where both of A⁵ and A⁶ represent a single bond. In this case, more preferred combinations include cases where R² represents a cyclopropyl group, a cyclobutyl group, a cyclopropylmethyl group, a methyl group, an ethyl group, a vinyl group, an isopropyl group, an isobutyl group or 2-methyl-1-propenyl group, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group optionally substituted with one alkyl group having 1 to 4 carbon atoms or one halogen atom.

Also combinations wherein both of A⁵ and A⁶ represent a single bond, and R² represents a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, a C₂-C₄ acyl group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group or phenyl group which may be substituted by one or more of a fluorine atom or a chlorine atom, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group which may be substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom can be mentioned as preferred examples.

Further, an explanation will be given of preferred combinations of A¹-G² portion, R²-A⁵ portion and R³-A⁶ portion in the formula (I). Basically, preferably those mentioned as preferred examples for A¹-G² portion, R²-A⁵ portion and R³-A⁶ portion are combined, and more preferably more preferred examples are combined.

More specifically, in the combinations of the following a) to f) mentioned as preferred combinations of the A¹-G² portion, further a case where both of A⁵ and A⁶ represent a single bond is preferred.

a) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)— or —NH—(C═O)—NH—, G¹ represents a single bond, and A³ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms.

b) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)—, —NH—(C═O)—NH—, —NH—, or —C—(═O)—NH—, and G¹ represents a group other than the single bond.

c) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents a single bond, and G¹ represents an optionally substituted heterocyclic group (note, where a heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, 5 or 6 membered monocyclic heterocyclic group of G¹ is substituted, or A³-G² portion represents those other than a hydrogen atom).

d) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, and G¹ represents an optionally substituted aromatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group having 7 to 10 carbon atoms, or an optionally substituted heterocyclic group (note, where the aromatic hydrocarbon group of G¹ is a phenyl group, or where the heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, the phenyl group of G¹ or 5 or 6 membered monocyclic heterocyclic group is substituted, or A³-G² portion represents those other than a hydrogen atom).

e) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, G¹ and A⁴ represent the single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, G² represents an optionally substituted alicyclic hydrocarbon group having 5 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group, or optionally substituted heterocyclic group.

f) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, —specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, G¹ represents the single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, and A⁴ represents —C(═O)—, —C(═O)—NR¹²¹—, —C(═S)—NR¹²²—, —C(═NR¹²³)—, —O—C(═O)—, —NR¹²⁵—C(═O)—, —NR¹²⁶ —S(═O)₂—, —NR¹²⁷—C(═O)—O—, —NR¹²⁸—C(═O)—NR¹²⁹—, —NR¹³⁰—C(═S)—, —NR¹³¹—C(═S)—NR¹³²—, —S—, —S(═O)—, —S(═O)₂—, —S(═O)₂—NR¹³³— or —S(═O)₂—O—.

In the cases of d) to f), A² preferably represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—, especially preferably represents —C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

In these cases of combinations, further preferably R² represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms or an optionally substituted heterocyclic group, and R³ represents an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms or an optionally substituted heterocyclic group.

In further detail, in these cases, combinations wherein R² represents an aliphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted phenyl group, or an optionally substituted heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, and R³ represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group or a phenyl group optionally substituted with one or more alkyl group having 1 to 4 carbon atoms are specifically preferred. Especially, preferred combinations can include cases where R² represents a cyclopropyl group, a methyl group, an ethyl group, a vinyl group, an isopropyl group, an isobutyl group or 2-methyl-1-propenyl group, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group which may be substituted by an alkyl group having 1 to 4 carbon atoms or one halogen atom, and cases where R² represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group or phenyl group which may be substituted by one or more of a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, and a chlorine group, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group which may be substituted by an alkyl group having 1 to 4 carbon atoms or one halogen atom.

In the pyrrolo-pyrimidinone derivatives of the formula (I), specific preferred combinations of -G¹-A³-A⁴-G² portion include groups represented by the following formulae, K001-K431. In the respective chemical formula, symbol “ - - -” is used to denote a binding site between A² and the group -G¹-A³-A⁴-G².

In the pyrrolo-pyrimidinone derivatives of the formula (I), as specific examples of preferred combinations of the -A⁵-R² portion, groups represented by the following formulae, J001-J166 may be mentioned. In the respective chemical formulae, symbol “ - - -” indicates a binding site between a carbon atom of a pyrrole ring and -A⁵-R².

In the pyrrolo-pyrimidinone derivatives of the formula (I), as specific examples of preferred combinations of the -A⁶-R³ portion, groups represented by the following formulae, T001-T181 may be mentioned. In the respective chemical formulae, symbol “ - - -” indicates a binding site between a carbon atom of a pyrrole ring and -A⁶-R³.

Specific examples of the pyrrolo-pyrimidinone derivatives of formula (I) include the compounds having groups described in the following Table 1 as A¹, the compounds having groups described in the following Table 1 as A², the compounds having groups represented by K001-K431 indicated in the formula as -G¹-A³-A⁴-G², the compounds having groups represented by J01-J166 indicated in the formula as -A⁵-R², the compounds having groups represented by T001-T181 indicated in the formula as -A⁶-R³, and the compounds consisting of any combination of groups mentioned above with regard to each moiety. Preferable examples among such compounds are listed in Tables below. TABLE 1 Compound no. -A¹- -A²- -G¹-A³-A⁴-G² -A⁵-R² -A⁶-R³ 1 —(CH₂)₂— —C(═O)— K002 J001 T148 2 —(CH₂)₂— —C(═O)— K002 J001 T151 3 —(CH₂)₂— —C(═O)— K003 J001 T148 4 —(CH₂)₂— —C(═O)— K003 J001 T151 5 —(CH₂)₂— —C(═O)— K004 J001 T148 6 —(CH₂)₂— —C(═O)— K004 J001 T151 7 —(CH₂)₂— —C(═O)— K005 J001 T148 8 —(CH₂)₂— —C(═O)— K005 J001 T151 9 —(CH₂)₂— —C(═O)— K007 J001 T148 10 —(CH₂)₂— —C(═O)— K007 J001 T152 11 —(CH₂)₂— —C(═O)— K008 J001 T148 12 —(CH₂)₂— —C(═O)— K008 J001 T152 13 —(CH₂)₂— —C(═O)— K009 J001 T148 14 —(CH₂)₂— —C(═O)— K009 J001 T152 15 —(CH₂)₂— —C(═O)— K012 J001 T148 16 —(CH₂)₂— —C(═O)— K012 J001 T152 17 —(CH₂)₂— —C(═O)— K107 J001 T148 18 —(CH₂)₂— —C(═O)— K107 J001 T168 19 —(CH₂)₂— —C(═O)— K108 J001 T148 20 —(CH₂)₂— —C(═O)— K108 J001 T169 21 —(CH₂)₂— —C(═O)— K112 J001 T148 22 —(CH₂)₂— —C(═O)— K112 J001 T170 23 —(CH₂)₂— —C(═O)— K129 J001 T148 24 —(CH₂)₂— —C(═O)— K129 J001 T171 25 —(CH₂)₂— —C(═O)— K133 J001 T148 26 —(CH₂)₂— —C(═O)— K133 J001 T172 27 —(CH₂)₂— —C(═O)— K137 J001 T148 28 —(CH₂)₂— —C(═O)— K137 J001 T173 29 —(CH₂)₂— —C(═O)—NH— K007 J001 T148 30 —(CH₂)₂— —C(═O)—NH— K012 J001 T148 31 —(CH₂)₂— —C(═O)—O— K001 J001 T148 32 —(CH₂)₂— —C(═O)—O— K002 J001 T151 33 —(CH₂)₂— —C(═O)—O— K193 J001 T152 34 —(CH₂)₂— —C(═O)—O— K227 J001 T169 35 —(CH₂)₂— —C(═O)—O— K002 J001 T148 36 —(CH₂)₂— —NH— K181 J012 T148 37 —(CH₂)₂— —NH— K181 J012 T151 38 —(CH₂)₂— —NH— K181 J012 T152 39 —(CH₂)₂— —NH— K181 J012 T169 40 —(CH₂)₂— —NH— K181 J045 T148 41 —(CH₂)₂— —NH— K181 J045 T151 42 —(CH₂)₂— —NH— K181 J045 T152 43 —(CH₂)₂— —NH— K181 J045 T169 44 —(CH₂)₂— —NH— K181 J045 T170 45 —(CH₂)₂— —NH— K181 J045 T172 46 —(CH₂)₂— —NH— K182 J012 T148 47 —(CH₂)₂— —NH— K182 J012 T151 48 —(CH₂)₂— —NH— K182 J012 T152 49 —(CH₂)₂— —NH— K182 J012 T169 50 —(CH₂)₂— —NH— K182 J045 T148 51 —(CH₂)₂— —NH— K182 J045 T151 52 —(CH₂)₂— —NH— K182 J045 T152 53 —(CH₂)₂— —NH— K182 J045 T169 54 —(CH₂)₂— —NH— K182 J045 T170 55 —(CH₂)₂— —NH— K182 J045 T172 56 —(CH₂)₂— —NH— K183 J012 T148 57 —(CH₂)₂— —NH— K183 J012 T151 58 —(CH₂)₂— —NH— K183 J012 T152 59 —(CH₂)₂— —NH— K183 J012 T169 60 —(CH₂)₂— —NH— K183 J045 T148 61 —(CH₂)₂— —NH— K183 J045 T151 62 —(CH₂)₂— —NH— K183 J045 T152 63 —(CH₂)₂— —NH— K183 J045 T169 64 —(CH₂)₂— —NH— K183 J045 T170 65 —(CH₂)₂— —NH— K183 J045 T172 66 —(CH₂)₂— —NH— K184 J012 T148 67 —(CH₂)₂— —NH— K184 J012 T151 68 —(CH₂)₂— —NH— K184 J012 T152 69 —(CH₂)₂— —NH— K184 J012 T169 70 —(CH₂)₂— —NH— K184 J045 T148 71 —(CH₂)₂— —NH— K184 J045 T151 72 —(CH₂)₂— —NH— K184 J045 T152 73 —(CH₂)₂— —NH— K184 J045 T169 74 —(CH₂)₂— —NH— K184 J045 T170 75 —(CH₂)₂— —NH— K184 J045 T172 76 —(CH₂)₂— —NH— K185 J012 T148 77 —(CH₂)₂— —NH— K185 J012 T151 78 —(CH₂)₂— —NH— K185 J012 T152 79 —(CH₂)₂— —NH— K185 J012 T169 80 —(CH₂)₂— —NH— K185 J045 T004 81 —(CH₂)₂— —NH— K185 J045 T005 82 —(CH₂)₂— —NH— K185 J045 T090 83 —(CH₂)₂— —NH— K185 J045 T129 84 —(CH₂)₂— —NH— K185 J045 T148 85 —(CH₂)₂— —NH— K185 J045 T151 86 —(CH₂)₂— —NH— K185 J045 T152 87 —(CH₂)₂— —NH— K185 J045 T169 88 —(CH₂)₂— —NH— K185 J045 T170 89 —(CH₂)₂— —NH— K185 J045 T172 90 —(CH₂)₂— —NH— K186 J012 T148 91 —(CH₂)₂— —NH— K186 J012 T151 92 —(CH₂)₂— —NH— K186 J012 T152 93 —(CH₂)₂— —NH— K186 J012 T169 94 —(CH₂)₂— —NH— K186 J045 T148 95 —(CH₂)₂— —NH— K186 J045 T151 96 —(CH₂)₂— —NH— K186 J045 T152 97 —(CH₂)₂— —NH— K186 J045 T169 98 —(CH₂)₂— —NH— K186 J045 T170 99 —(CH₂)₂— —NH— K186 J045 T172 100 —(CH₂)₂— —NH— K187 J012 T148 101 —(CH₂)₂— —NH— K187 J012 T151 102 —(CH₂)₂— —NH— K187 J012 T152 103 —(CH₂)₂— —NH— K187 J012 T169 104 —(CH₂)₂— —NH— K187 J045 T148 105 —(CH₂)₂— —NH— K187 J045 T151 106 —(CH₂)₂— —NH— K187 J045 T152 107 —(CH₂)₂— —NH— K187 J045 T169 108 —(CH₂)₂— —NH— K187 J045 T170 109 —(CH₂)₂— —NH— K187 J045 T172 110 —(CH₂)₂— —NH— K188 J012 T148 111 —(CH₂)₂— —NH— K188 J012 T151 112 —(CH₂)₂— —NH— K188 J012 T152 113 —(CH₂)₂— —NH— K188 J012 T169 114 —(CH₂)₂— —NH— K188 J045 T148 115 —(CH₂)₂— —NH— K188 J045 T151 116 —(CH₂)₂— —NH— K188 J045 T152 117 —(CH₂)₂— —NH— K188 J045 T169 118 —(CH₂)₂— —NH— K188 J045 T170 119 —(CH₂)₂— —NH— K188 J045 T172 120 —(CH₂)₂— —NH— K189 J012 T148 121 —(CH₂)₂— —NH— K189 J012 T151 122 —(CH₂)₂— —NH— K189 J012 T152 123 —(CH₂)₂— —NH— K189 J012 T169 124 —(CH₂)₂— —NH— K189 J045 T148 125 —(CH₂)₂— —NH— K189 J045 T151 126 —(CH₂)₂— —NH— K189 J045 T152 127 —(CH₂)₂— —NH— K189 J045 T169 128 —(CH₂)₂— —NH— K189 J045 T170 129 —(CH₂)₂— —NH— K189 J045 T172 130 —(CH₂)₂— —NH— K190 J012 T148 131 —(CH₂)₂— —NH— K190 J012 T151 132 —(CH₂)₂— —NH— K190 J012 T152 133 —(CH₂)₂— —NH— K190 J012 T169 134 —(CH₂)₂— —NH— K190 J045 T148 135 —(CH₂)₂— —NH— K190 J045 T151 136 —(CH₂)₂— —NH— K190 J045 T152 137 —(CH₂)₂— —NH— K190 J045 T169 138 —(CH₂)₂— —NH— K190 J045 T170 139 —(CH₂)₂— —NH— K190 J045 T172 140 —(CH₂)₂— —NH— K191 J012 T148 141 —(CH₂)₂— —NH— K191 J012 T151 142 —(CH₂)₂— —NH— K191 J012 T152 143 —(CH₂)₂— —NH— K191 J012 T169 144 —(CH₂)₂— —NH— K191 J045 T148 145 —(CH₂)₂— —NH— K191 J045 T151 146 —(CH₂)₂— —NH— K191 J045 T152 147 —(CH₂)₂— —NH— K191 J045 T169 148 —(CH₂)₂— —NH— K191 J045 T170 149 —(CH₂)₂— —NH— K191 J045 T172 150 —(CH₂)₂— —NH— K192 J012 T148 151 —(CH₂)₂— —NH— K192 J012 T151 152 —(CH₂)₂— —NH— K192 J012 T152 153 —(CH₂)₂— —NH— K192 J012 T169 154 —(CH₂)₂— —NH— K192 J045 T148 155 —(CH₂)₂— —NH— K192 J045 T151 156 —(CH₂)₂— —NH— K192 J045 T152 157 —(CH₂)₂— —NH— K192 J045 T169 158 —(CH₂)₂— —NH— K192 J045 T170 159 —(CH₂)₂— —NH— K192 J045 T172 160 —(CH₂)₂— —NH— K193 J012 T148 161 —(CH₂)₂— —NH— K193 J012 T151 162 —(CH₂)₂— —NH— K193 J012 T152 163 —(CH₂)₂— —NH— K193 J012 T169 164 —(CH₂)₂— —NH— K193 J045 T148 165 —(CH₂)₂— —NH— K193 J045 T151 166 —(CH₂)₂— —NH— K193 J045 T152 167 —(CH₂)₂— —NH— K193 J045 T169 168 —(CH₂)₂— —NH— K193 J045 T170 169 —(CH₂)₂— —NH— K193 J045 T172 170 —(CH₂)₂— —NH— K194 J012 T148 171 —(CH₂)₂— —NH— K194 J012 T151 172 —(CH₂)₂— —NH— K194 J012 T152 173 —(CH₂)₂— —NH— K194 J012 T169 174 —(CH₂)₂— —NH— K194 J045 T148 175 —(CH₂)₂— —NH— K194 J045 T151 176 —(CH₂)₂— —NH— K194 J045 T152 177 —(CH₂)₂— —NH— K194 J045 T169 178 —(CH₂)₂— —NH— K194 J045 T170 179 —(CH₂)₂— —NH— K194 J045 T172 180 —(CH₂)₂— —NH— K195 J012 T148 181 —(CH₂)₂— —NH— K195 J012 T151 182 —(CH₂)₂— —NH— K195 J012 T152 183 —(CH₂)₂— —NH— K195 J012 T169 184 —(CH₂)₂— —NH— K195 J045 T148 185 —(CH₂)₂— —NH— K195 J045 T151 186 —(CH₂)₂— —NH— K195 J045 T152 187 —(CH₂)₂— —NH— K195 J045 T169 188 —(CH₂)₂— —NH— K195 J045 T170 189 —(CH₂)₂— —NH— K195 J045 T172 190 —(CH₂)₂— —NH— K196 J012 T148 191 —(CH₂)₂— —NH— K196 J012 T151 192 —(CH₂)₂— —NH— K196 J012 T152 193 —(CH₂)₂— —NH— K196 J012 T169 194 —(CH₂)₂— —NH— K196 J045 T148 195 —(CH₂)₂— —NH— K196 J045 T151 196 —(CH₂)₂— —NH— K196 J045 T152 197 —(CH₂)₂— —NH— K196 J045 T169 198 —(CH₂)₂— —NH— K196 J045 T170 199 —(CH₂)₂— —NH— K196 J045 T172 200 —(CH₂)₂— —NH— K197 J012 T148 201 —(CH₂)₂— —NH— K197 J012 T151 202 —(CH₂)₂— —NH— K197 J012 T152 203 —(CH₂)₂— —NH— K197 J012 T169 204 —(CH₂)₂— —NH— K197 J045 T003 205 —(CH₂)₂— —NH— K197 J045 T004 206 —(CH₂)₂— —NH— K197 J045 T005 207 —(CH₂)₂— —NH— K197 J045 T077 208 —(CH₂)₂— —NH— K197 J045 T090 209 —(CH₂)₂— —NH— K197 J045 T148 210 —(CH₂)₂— —NH— K197 J045 T151 211 —(CH₂)₂— —NH— K197 J045 T152 212 —(CH₂)₂— —NH— K197 J045 T161 213 —(CH₂)₂— —NH— K197 J045 T169 214 —(CH₂)₂— —NH— K197 J045 T170 215 —(CH₂)₂— —NH— K197 J045 T172 216 —(CH₂)₂— —NH—C(═O)— K001 J001 T129 217 —(CH₂)₂— —NH—C(═O)— K001 J045 T148 218 —(CH₂)₂— —NH—C(═O)— K002 J002 T130 219 —(CH₂)₂— —NH—C(═O)— K002 J045 T148 220 —(CH₂)₂— —NH—C(═O)— K003 J001 T148 221 —(CH₂)₂— —NH—C(═O)— K003 J001 T169 222 —(CH₂)₂— —NH—C(═O)— K003 J008 T134 223 —(CH₂)₂— —NH—C(═O)— K003 J008 T148 224 —(CH₂)₂— —NH—C(═O)— K003 J009 T148 225 —(CH₂)₂— —NH—C(═O)— K003 J012 T148 226 —(CH₂)₂— —NH—C(═O)— K003 J018 T148 227 —(CH₂)₂— —NH—C(═O)— K003 J018 T152 228 —(CH₂)₂— —NH—C(═O)— K003 J035 T148 229 —(CH₂)₂— —NH—C(═O)— K003 J035 T151 230 —(CH₂)₂— —NH—C(═O)— K003 J045 T148 231 —(CH₂)₂— —NH—C(═O)— K003 J052 T148 232 —(CH₂)₂— —NH—C(═O)— K003 J052 T169 233 —(CH₂)₂— —NH—C(═O)— K003 J069 T148 234 —(CH₂)₂— —NH—C(═O)— K003 J069 T152 235 —(CH₂)₂— —NH—C(═O)— K004 J003 T148 236 —(CH₂)₂— —NH—C(═O)— K004 J003 T152 237 —(CH₂)₂— —NH—C(═O)— K004 J008 T148 238 —(CH₂)₂— —NH—C(═O)— K004 J009 T135 239 —(CH₂)₂— —NH—C(═O)— K004 J009 T148 240 —(CH₂)₂— —NH—C(═O)— K004 J012 T148 241 —(CH₂)₂— —NH—C(═O)— K004 J020 T148 242 —(CH₂)₂— —NH—C(═O)— K004 J020 T151 243 —(CH₂)₂— —NH—C(═O)— K004 J037 T148 244 —(CH₂)₂— —NH—C(═O)— K004 J037 T169 245 —(CH₂)₂— —NH—C(═O)— K004 J045 T148 246 —(CH₂)₂— —NH—C(═O)— K004 J054 T148 247 —(CH₂)₂— —NH—C(═O)— K004 J054 T152 248 —(CH₂)₂— —NH—C(═O)— K004 J071 T148 249 —(CH₂)₂— —NH—C(═O)— K004 J071 T151 250 —(CH₂)₂— —NH—C(═O)— K005 J008 T148 251 —(CH₂)₂— —NH—C(═O)— K005 J009 T148 252 —(CH₂)₂— —NH—C(═O)— K005 J012 T145 253 —(CH₂)₂— —NH—C(═O)— K005 J012 T148 254 —(CH₂)₂— —NH—C(═O)— K005 J045 T148 255 —(CH₂)₂— —NH—C(═O)— K006 J008 T148 256 —(CH₂)₂— —NH—C(═O)— K006 J009 T148 257 —(CH₂)₂— —NH—C(═O)— K006 J012 T148 258 —(CH₂)₂— —NH—C(═O)— K006 J014 T148 259 —(CH₂)₂— —NH—C(═O)— K007 J004 T148 260 —(CH₂)₂— —NH—C(═O)— K007 J004 T169 261 —(CH₂)₂— —NH—C(═O)— K007 J008 T148 262 —(CH₂)₂— —NH—C(═O)— K007 J009 T148 263 —(CH₂)₂— —NH—C(═O)— K007 J012 T148 264 —(CH₂)₂— —NH—C(═O)— K007 J015 T149 265 —(CH₂)₂— —NH—C(═O)— K007 J021 T148 266 —(CH₂)₂— —NH—C(═O)— K007 J021 T152 267 —(CH₂)₂— —NH—C(═O)— K007 J038 T148 268 —(CH₂)₂— —NH—C(═O)— K007 J038 T151 269 —(CH₂)₂— —NH—C(═O)— K007 J045 T148 270 —(CH₂)₂— —NH—C(═O)— K007 J055 T148 271 —(CH₂)₂— —NH—C(═O)— K007 J055 T169 272 —(CH₂)₂— —NH—C(═O)— K007 J072 T148 273 —(CH₂)₂— —NH—C(═O)— K007 J072 T152 274 —(CH₂)₂— —NH—C(═O)— K008 J005 T148 275 —(CH₂)₂— —NH—C(═O)— K008 J005 T151 276 —(CH₂)₂— —NH—C(═O)— K008 J008 T148 277 —(CH₂)₂— —NH—C(═O)— K008 J008 T152 278 —(CH₂)₂— —NH—C(═O)— K008 J009 T148 279 —(CH₂)₂— —NH—C(═O)— K008 J009 T152 280 —(CH₂)₂— —NH—C(═O)— K008 J012 T148 281 —(CH₂)₂— —NH—C(═O)— K008 J012 T152 282 —(CH₂)₂— —NH—C(═O)— K008 J018 T151 283 —(CH₂)₂— —NH—C(═O)— K008 J022 T148 284 —(CH₂)₂— —NH—C(═O)— K008 J022 T169 285 —(CH₂)₂— —NH—C(═O)— K008 J039 T148 286 —(CH₂)₂— —NH—C(═O)— K008 J039 T152 287 —(CH₂)₂— —NH—C(═O)— K008 J045 T148 288 —(CH₂)₂— —NH—C(═O)— K008 J045 T152 289 —(CH₂)₂— —NH—C(═O)— K008 J056 T148 290 —(CH₂)₂— —NH—C(═O)— K008 J056 T151 291 —(CH₂)₂— —NH—C(═O)— K008 J073 T148 292 —(CH₂)₂— —NH—C(═O)— K008 J073 T169 293 —(CH₂)₂— —NH—C(═O)— K009 J006 T148 294 —(CH₂)₂— —NH—C(═O)— K009 J006 T152 295 —(CH₂)₂— —NH—C(═O)— K009 J008 T148 296 —(CH₂)₂— —NH—C(═O)— K009 J009 T148 297 —(CH₂)₂— —NH—C(═O)— K009 J012 T148 298 —(CH₂)₂— —NH—C(═O)— K009 J023 T148 299 —(CH₂)₂— —NH—C(═O)— K009 J023 T151 300 —(CH₂)₂— —NH—C(═O)— K009 J040 T148 301 —(CH₂)₂— —NH—C(═O)— K009 J040 T169 302 —(CH₂)₂— —NH—C(═O)— K009 J043 T152 303 —(CH₂)₂— —NH—C(═O)— K009 J045 T148 304 —(CH₂)₂— —NH—C(═O)— K009 J057 T148 305 —(CH₂)₂— —NH—C(═O)— K009 J057 T152 306 —(CH₂)₂— —NH—C(═O)— K009 J074 T148 307 —(CH₂)₂— —NH—C(═O)— K009 J074 T151 308 —(CH₂)₂— —NH—C(═O)— K010 J045 T157 309 —(CH₂)₂— —NH—C(═O)— K011 J007 T148 310 —(CH₂)₂— —NH—C(═O)— K011 J007 T169 311 —(CH₂)₂— —NH—C(═O)— K011 J008 T148 312 —(CH₂)₂— —NH—C(═O)— K011 J009 T148 313 —(CH₂)₂— —NH—C(═O)— K011 J012 T148 314 —(CH₂)₂— —NH—C(═O)— K011 J024 T148 315 —(CH₂)₂— —NH—C(═O)— K011 J024 T152 316 —(CH₂)₂— —NH—C(═O)— K011 J041 T148 317 —(CH₂)₂— —NH—C(═O)— K011 J041 T151 318 —(CH₂)₂— —NH—C(═O)— K011 J045 T003 319 —(CH₂)₂— —NH—C(═O)— K011 J045 T004 320 —(CH₂)₂— —NH—C(═O)— K011 J045 T005 321 —(CH₂)₂— —NH—C(═O)— K011 J045 T148 322 —(CH₂)₂— —NH—C(═O)— K011 J058 T148 323 —(CH₂)₂— —NH—C(═O)— K011 J058 T169 324 —(CH₂)₂— —NH—C(═O)— K011 J063 T158 325 —(CH₂)₂— —NH—C(═O)— K011 J075 T148 326 —(CH₂)₂— —NH—C(═O)— K011 J075 T152 327 —(CH₂)₂— —NH—C(═O)— K012 J008 T148 328 —(CH₂)₂— —NH—C(═O)— K012 J008 T151 329 —(CH₂)₂— —NH—C(═O)— K012 J009 T148 330 —(CH₂)₂— —NH—C(═O)— K012 J012 T148 331 —(CH₂)₂— —NH—C(═O)— K012 J025 T148 332 —(CH₂)₂— —NH—C(═O)— K012 J025 T169 333 —(CH₂)₂— —NH—C(═O)— K012 J042 T148 334 —(CH₂)₂— —NH—C(═O)— K012 J042 T152 335 —(CH₂)₂— —NH—C(═O)— K012 J045 T148 336 —(CH₂)₂— —NH—C(═O)— K012 J059 T148 337 —(CH₂)₂— —NH—C(═O)— K012 J059 T151 338 —(CH₂)₂— —NH—C(═O)— K012 J076 T148 339 —(CH₂)₂— —NH—C(═O)— K012 J076 T169 340 —(CH₂)₂— —NH—C(═O)— K012 J081 T164 341 —(CH₂)₂— —NH—C(═O)— K013 J001 T168 342 —(CH₂)₂— —NH—C(═O)— K013 J008 T148 343 —(CH₂)₂— —NH—C(═O)— K013 J012 T148 344 —(CH₂)₂— —NH—C(═O)— K013 J045 T005 345 —(CH₂)₂— —NH—C(═O)— K013 J045 T077 346 —(CH₂)₂— —NH—C(═O)— K013 J045 T090 347 —(CH₂)₂— —NH—C(═O)— K013 J045 T129 348 —(CH₂)₂— —NH—C(═O)— K013 J045 T148 349 —(CH₂)₂— —NH—C(═O)— K014 J002 T169 350 —(CH₂)₂— —NH—C(═O)— K015 J008 T170 351 —(CH₂)₂— —NH—C(═O)— K016 J009 T173 352 —(CH₂)₂— —NH—C(═O)— K017 J012 T176 353 —(CH₂)₂— —NH—C(═O)— K018 J014 T178 354 —(CH₂)₂— —NH—C(═O)— K019 J015 T129 355 —(CH₂)₂— —NH—C(═O)— K020 J018 T130 356 —(CH₂)₂— —NH—C(═O)— K021 J043 T134 357 —(CH₂)₂— —NH—C(═O)— K022 J045 T135 358 —(CH₂)₂— —NH—C(═O)— K023 J063 T145 359 —(CH₂)₂— —NH—C(═O)— K024 J081 T148 360 —(CH₂)₂— —NH—C(═O)— K025 J001 T149 361 —(CH₂)₂— —NH—C(═O)— K025 J045 T148 362 —(CH₂)₂— —NH—C(═O)— K026 J002 T151 363 —(CH₂)₂— —NH—C(═O)— K027 J008 T152 364 —(CH₂)₂— —NH—C(═O)— K028 J009 T157 365 —(CH₂)₂— —NH—C(═O)— K029 J012 T158 366 —(CH₂)₂— —NH—C(═O)— K030 J014 T164 367 —(CH₂)₂— —NH—C(═O)— K031 J015 T168 368 —(CH₂)₂— —NH—C(═O)— K032 J018 T169 369 —(CH₂)₂— —NH—C(═O)— K033 J043 T170 370 —(CH₂)₂— —NH—C(═O)— K033 J045 T004 371 —(CH₂)₂— —NH—C(═O)— K034 J045 T173 372 —(CH₂)₂— —NH—C(═O)— K035 J063 T176 373 —(CH₂)₂— —NH—C(═O)— K036 J081 T178 374 —(CH₂)₂— —NH—C(═O)— K037 J001 T129 375 —(CH₂)₂— —NH—C(═O)— K038 J002 T130 376 —(CH₂)₂— —NH—C(═O)— K039 J008 T134 377 —(CH₂)₂— —NH—C(═O)— K040 J009 T135 378 —(CH₂)₂— —NH—C(═O)— K041 J012 T145 379 —(CH₂)₂— —NH—C(═O)— K042 J014 T148 380 —(CH₂)₂— —NH—C(═O)— K043 J015 T149 381 —(CH₂)₂— —NH—C(═O)— K044 J010 T148 382 —(CH₂)₂— —NH—C(═O)— K044 J010 T169 383 —(CH₂)₂— —NH—C(═O)— K044 J018 T151 384 —(CH₂)₂— —NH—C(═O)— K044 J027 T148 385 —(CH₂)₂— —NH—C(═O)— K044 J027 T152 386 —(CH₂)₂— —NH—C(═O)— K044 J044 T148 387 —(CH₂)₂— —NH—C(═O)— K044 J044 T151 388 —(CH₂)₂— —NH—C(═O)— K044 J061 T148 389 —(CH₂)₂— —NH—C(═O)— K044 J061 T169 390 —(CH₂)₂— —NH—C(═O)— K044 J078 T148 391 —(CH₂)₂— —NH—C(═O)— K044 J078 T152 392 —(CH₂)₂— —NH—C(═O)— K045 J043 T152 393 —(CH₂)₂— —NH—C(═O)— K046 J045 T157 394 —(CH₂)₂— —NH—C(═O)— K047 J063 T158 395 —(CH₂)₂— —NH—C(═O)— K048 J081 T164 396 —(CH₂)₂— —NH—C(═O)— K049 J001 T168 397 —(CH₂)₂— —NH—C(═O)— K050 J002 T169 398 —(CH₂)₂— —NH—C(═O)— K051 J008 T170 399 —(CH₂)₂— —NH—C(═O)— K052 J009 T173 400 —(CH₂)₂— —NH—C(═O)— K053 J012 T176 401 —(CH₂)₂— —NH—C(═O)— K054 J014 T178 402 —(CH₂)₂— —NH—C(═O)— K055 J015 T129 403 —(CH₂)₂— —NH—C(═O)— K056 J018 T130 404 —(CH₂)₂— —NH—C(═O)— K057 J043 T134 405 —(CH₂)₂— —NH—C(═O)— K058 J045 T135 406 —(CH₂)₂— —NH—C(═O)— K059 J063 T145 407 —(CH₂)₂— —NH—C(═O)— K060 J081 T148 408 —(CH₂)₂— —NH—C(═O)— K061 J001 T149 409 —(CH₂)₂— —NH—C(═O)— K062 J002 T151 410 —(CH₂)₂— —NH—C(═O)— K063 J008 T152 411 —(CH₂)₂— —NH—C(═O)— K064 J009 T157 412 —(CH₂)₂— —NH—C(═O)— K065 J012 T158 413 —(CH₂)₂— —NH—C(═O)— K066 J014 T164 414 —(CH₂)₂— —NH—C(═O)— K067 J015 T168 415 —(CH₂)₂— —NH—C(═O)— K068 J018 T169 416 —(CH₂)₂— —NH—C(═O)— K069 J043 T170 417 —(CH₂)₂— —NH—C(═O)— K070 J011 T148 418 —(CH₂)₂— —NH—C(═O)— K070 J011 T151 419 —(CH₂)₂— —NH—C(═O)— K070 J028 T148 420 —(CH₂)₂— —NH—C(═O)— K070 J028 T169 421 —(CH₂)₂— —NH—C(═O)— K070 J045 T148 422 —(CH₂)₂— —NH—C(═O)— K070 J045 T152 423 —(CH₂)₂— —NH—C(═O)— K070 J045 T173 424 —(CH₂)₂— —NH—C(═O)— K070 J062 T148 425 —(CH₂)₂— —NH—C(═O)— K070 J062 T151 426 —(CH₂)₂— —NH—C(═O)— K070 J079 T148 427 —(CH₂)₂— —NH—C(═O)— K070 J079 T169 428 —(CH₂)₂— —NH—C(═O)— K071 J063 T176 429 —(CH₂)₂— —NH—C(═O)— K072 J012 T148 430 —(CH₂)₂— —NH—C(═O)— K072 J012 T152 431 —(CH₂)₂— —NH—C(═O)— K072 J029 T148 432 —(CH₂)₂— —NH—C(═O)— K072 J029 T151 433 —(CH₂)₂— —NH—C(═O)— K072 J046 T148 434 —(CH₂)₂— —NH—C(═O)— K072 J046 T169 435 —(CH₂)₂— —NH—C(═O)— K072 J063 T148 436 —(CH₂)₂— —NH—C(═O)— K072 J063 T152 437 —(CH₂)₂— —NH—C(═O)— K072 J080 T148 438 —(CH₂)₂— —NH—C(═O)— K072 J080 T151 439 —(CH₂)₂— —NH—C(═O)— K072 J081 T178 440 —(CH₂)₂— —NH—C(═O)— K073 J001 T129 441 —(CH₂)₂— —NH—C(═O)— K074 J002 T130 442 —(CH₂)₂— —NH—C(═O)— K075 J008 T134 443 —(CH₂)₂— —NH—C(═O)— K076 J009 T135 444 —(CH₂)₂— —NH—C(═O)— K077 J012 T145 445 —(CH₂)₂— —NH—C(═O)— K078 J014 T148 446 —(CH₂)₂— —NH—C(═O)— K079 J015 T149 447 —(CH₂)₂— —NH—C(═O)— K080 J018 T151 448 —(CH₂)₂— —NH—C(═O)— K081 J043 T152 449 —(CH₂)₂— —NH—C(═O)— K082 J045 T157 450 —(CH₂)₂— —NH—C(═O)— K083 J063 T158 451 —(CH₂)₂— —NH—C(═O)— K084 J081 T164 452 —(CH₂)₂— —NH—C(═O)— K085 J001 T168 453 —(CH₂)₂— —NH—C(═O)— K086 J002 T169 454 —(CH₂)₂— —NH—C(═O)— K087 J008 T170 455 —(CH₂)₂— —NH—C(═O)— K088 J009 T173 456 —(CH₂)₂— —NH—C(═O)— K089 J012 T176 457 —(CH₂)₂— —NH—C(═O)— K090 J014 T178 458 —(CH₂)₂— —NH—C(═O)— K091 J015 T129 459 —(CH₂)₂— —NH—C(═O)— K092 J018 T130 460 —(CH₂)₂— —NH—C(═O)— K093 J043 T134 461 —(CH₂)₂— —NH—C(═O)— K094 J045 T135 462 —(CH₂)₂— —NH—C(═O)— K095 J063 T145 463 —(CH₂)₂— —NH—C(═O)— K096 J081 T148 464 —(CH₂)₂— —NH—C(═O)— K097 J001 T149 465 —(CH₂)₂— —NH—C(═O)— K098 J002 T151 466 —(CH₂)₂— —NH—C(═O)— K099 J008 T152 467 —(CH₂)₂— —NH—C(═O)— K100 J009 T157 468 —(CH₂)₂— —NH—C(═O)— K101 J012 T158 469 —(CH₂)₂— —NH—C(═O)— K102 J014 T164 470 —(CH₂)₂— —NH—C(═O)— K103 J015 T168 471 —(CH₂)₂— —NH—C(═O)— K104 J018 T169 472 —(CH₂)₂— —NH—C(═O)— K105 J043 T170 473 —(CH₂)₂— —NH—C(═O)— K106 J045 T173 474 —(CH₂)₂— —NH—C(═O)— K107 J013 T148 475 —(CH₂)₂— —NH—C(═O)— K107 J013 T169 476 —(CH₂)₂— —NH—C(═O)— K107 J030 T148 477 —(CH₂)₂— —NH—C(═O)— K107 J030 T152 478 —(CH₂)₂— —NH—C(═O)— K107 J047 T148 479 —(CH₂)₂— —NH—C(═O)— K107 J047 T151 480 —(CH₂)₂— —NH—C(═O)— K107 J063 T176 481 —(CH₂)₂— —NH—C(═O)— K107 J064 T148 482 —(CH₂)₂— —NH—C(═O)— K107 J064 T169 483 —(CH₂)₂— —NH—C(═O)— K107 J081 T148 484 —(CH₂)₂— —NH—C(═O)— K107 J081 T152 485 —(CH₂)₂— —NH—C(═O)— K108 J008 T148 486 —(CH₂)₂— —NH—C(═O)— K108 J009 T148 487 —(CH₂)₂— —NH—C(═O)— K108 J012 T148 488 —(CH₂)₂— —NH—C(═O)— K108 J014 T148 489 —(CH₂)₂— —NH—C(═O)— K108 J014 T151 490 —(CH₂)₂— —NH—C(═O)— K108 J031 T148 491 —(CH₂)₂— —NH—C(═O)— K108 J031 T169 492 —(CH₂)₂— —NH—C(═O)— K108 J045 T148 493 —(CH₂)₂— —NH—C(═O)— K108 J048 T148 494 —(CH₂)₂— —NH—C(═O)— K108 J048 T152 495 —(CH₂)₂— —NH—C(═O)— K108 J065 T148 496 —(CH₂)₂— —NH—C(═O)— K108 J065 T151 497 —(CH₂)₂— —NH—C(═O)— K108 J081 T178 498 —(CH₂)₂— —NH—C(═O)— K108 J082 T148 499 —(CH₂)₂— —NH—C(═O)— K108 J082 T169 500 —(CH₂)₂— —NH—C(═O)— K109 J001 T129 501 —(CH₂)₂— —NH—C(═O)— K109 J008 T148 502 —(CH₂)₂— —NH—C(═O)— K109 J009 T148 503 —(CH₂)₂— —NH—C(═O)— K109 J012 T148 504 —(CH₂)₂— —NH—C(═O)— K109 J045 T148 505 —(CH₂)₂— —NH—C(═O)— K110 J002 T130 506 —(CH₂)₂— —NH—C(═O)— K111 J008 T134 507 —(CH₂)₂— —NH—C(═O)— K112 J009 T135 508 —(CH₂)₂— —NH—C(═O)— K113 J012 T145 509 —(CH₂)₂— —NH—C(═O)— K114 J014 T148 510 —(CH₂)₂— —NH—C(═O)— K115 J015 T149 511 —(CH₂)₂— —NH—C(═O)— K116 J018 T151 512 —(CH₂)₂— —NH—C(═O)— K117 J043 T152 513 —(CH₂)₂— —NH—C(═O)— K118 J045 T157 514 —(CH₂)₂— —NH—C(═O)— K119 J063 T158 515 —(CH₂)₂— —NH—C(═O)— K120 J081 T164 516 —(CH₂)₂— —NH—C(═O)— K121 J001 T168 517 —(CH₂)₂— —NH—C(═O)— K122 J002 T169 518 —(CH₂)₂— —NH—C(═O)— K123 J008 T170 519 —(CH₂)₂— —NH—C(═O)— K124 J009 T173 520 —(CH₂)₂— —NH—C(═O)— K125 J012 T176 521 —(CH₂)₂— —NH—C(═O)— K126 J014 T178 522 —(CH₂)₂— —NH—C(═O)— K127 J015 T129 523 —(CH₂)₂— —NH—C(═O)— K128 J018 T130 524 —(CH₂)₂— —NH—C(═O)— K129 J043 T134 525 —(CH₂)₂— —NH—C(═O)— K130 J045 T135 526 —(CH₂)₂— —NH—C(═O)— K131 J063 T145 527 —(CH₂)₂— —NH—C(═O)— K132 J081 T148 528 —(CH₂)₂— —NH—C(═O)— K133 J001 T149 529 —(CH₂)₂— —NH—C(═O)— K134 J002 T151 530 —(CH₂)₂— —NH—C(═O)— K135 J008 T152 531 —(CH₂)₂— —NH—C(═O)— K136 J009 T157 532 —(CH₂)₂— —NH—C(═O)— K137 J008 T148 533 —(CH₂)₂— —NH—C(═O)— K137 J009 T148 534 —(CH₂)₂— —NH—C(═O)— K137 J012 T148 535 —(CH₂)₂— —NH—C(═O)— K137 J012 T158 536 —(CH₂)₂— —NH—C(═O)— K137 J045 T148 537 —(CH₂)₂— —NH—C(═O)— K138 J014 T164 538 —(CH₂)₂— —NH—C(═O)— K139 J015 T168 539 —(CH₂)₂— —NH—C(═O)— K140 J018 T169 540 —(CH₂)₂— —NH—C(═O)— K141 J043 T170 541 —(CH₂)₂— —NH—C(═O)— K142 J045 T173 542 —(CH₂)₂— —NH—C(═O)— K143 J063 T176 543 —(CH₂)₂— —NH—C(═O)— K144 J008 T148 544 —(CH₂)₂— —NH—C(═O)— K144 J009 T148 545 —(CH₂)₂— —NH—C(═O)— K144 J012 T148 546 —(CH₂)₂— —NH—C(═O)— K144 J015 T148 547 —(CH₂)₂— —NH—C(═O)— K144 J015 T152 548 —(CH₂)₂— —NH—C(═O)— K144 J032 T148 549 —(CH₂)₂— —NH—C(═O)— K144 J032 T151 550 —(CH₂)₂— —NH—C(═O)— K144 J045 T148 551 —(CH₂)₂— —NH—C(═O)— K144 J049 T148 552 —(CH₂)₂— —NH—C(═O)— K144 J049 T169 553 —(CH₂)₂— —NH—C(═O)— K144 J066 T148 554 —(CH₂)₂— —NH—C(═O)— K144 J066 T152 555 —(CH₂)₂— —NH—C(═O)— K144 J081 T178 556 —(CH₂)₂— —NH—C(═O)— K144 J083 T148 557 —(CH₂)₂— —NH—C(═O)— K144 J083 T151 558 —(CH₂)₂— —NH—C(═O)— K145 J001 T129 559 —(CH₂)₂— —NH—C(═O)— K146 J002 T130 560 —(CH₂)₂— —NH—C(═O)— K147 J008 T134 561 —(CH₂)₂— —NH—C(═O)— K148 J009 T135 562 —(CH₂)₂— —NH—C(═O)— K149 J012 T145 563 —(CH₂)₂— —NH—C(═O)— K150 J014 T148 564 —(CH₂)₂— —NH—C(═O)— K151 J015 T149 565 —(CH₂)₂— —NH—C(═O)— K152 J018 T151 566 —(CH₂)₂— —NH—C(═O)— K153 J043 T152 567 —(CH₂)₂— —NH—C(═O)— K154 J045 T157 568 —(CH₂)₂— —NH—C(═O)— K155 J063 T158 569 —(CH₂)₂— —NH—C(═O)— K156 J081 T164 570 —(CH₂)₂— —NH—C(═O)— K157 J001 T168 571 —(CH₂)₂— —NH—C(═O)— K158 J002 T169 572 —(CH₂)₂— —NH—C(═O)— K159 J008 T170 573 —(CH₂)₂— —NH—C(═O)— K160 J009 T173 574 —(CH₂)₂— —NH—C(═O)— K161 J012 T176 575 —(CH₂)₂— —NH—C(═O)— K162 J014 T178 576 —(CH₂)₂— —NH—C(═O)— K163 J015 T129 577 —(CH₂)₂— —NH—C(═O)— K164 J018 T130 578 —(CH₂)₂— —NH—C(═O)— K165 J043 T134 579 —(CH₂)₂— —NH—C(═O)— K166 J045 T135 580 —(CH₂)₂— —NH—C(═O)— K167 J063 T145 581 —(CH₂)₂— —NH—C(═O)— K168 J081 T148 582 —(CH₂)₂— —NH—C(═O)— K169 J001 T149 583 —(CH₂)₂— —NH—C(═O)— K170 J002 T151 584 —(CH₂)₂— —NH—C(═O)— K171 J008 T152 585 —(CH₂)₂— —NH—C(═O)— K172 J009 T157 586 —(CH₂)₂— —NH—C(═O)— K173 J012 T158 587 —(CH₂)₂— —NH—C(═O)— K174 J014 T164 588 —(CH₂)₂— —NH—C(═O)— K175 J015 T168 589 —(CH₂)₂— —NH—C(═O)— K176 J018 T169 590 —(CH₂)₂— —NH—C(═O)— K177 J043 T170 591 —(CH₂)₂— —NH—C(═O)— K178 J045 T173 592 —(CH₂)₂— —NH—C(═O)— K197 J063 T176 593 —(CH₂)₂— —NH—C(═O)— K198 J008 T148 594 —(CH₂)₂— —NH—C(═O)— K198 J009 T148 595 —(CH₂)₂— —NH—C(═O)— K198 J012 T148 596 —(CH₂)₂— —NH—C(═O)— K198 J045 T148 597 —(CH₂)₂— —NH—C(═O)— K198 J081 T178 598 —(CH₂)₂— —NH—C(═O)— K199 J001 T129 599 —(CH₂)₂— —NH—C(═O)— K199 J008 T148 600 —(CH₂)₂— —NH—C(═O)— K199 J009 T148 601 —(CH₂)₂— —NH—C(═O)— K199 J012 T148 602 —(CH₂)₂— —NH—C(═O)— K199 J045 T148 603 —(CH₂)₂— —NH—C(═O)— K200 J002 T130 604 —(CH₂)₂— —NH—C(═O)— K200 J008 T005 605 —(CH₂)₂— —NH—C(═O)— K200 J008 T148 606 —(CH₂)₂— —NH—C(═O)— K200 J008 T151 607 —(CH₂)₂— —NH—C(═O)— K200 J008 T152 608 —(CH₂)₂— —NH—C(═O)— K200 J008 T169 609 —(CH₂)₂— —NH—C(═O)— K200 J009 T005 610 —(CH₂)₂— —NH—C(═O)— K200 J009 T148 611 —(CH₂)₂— —NH—C(═O)— K200 J009 T151 612 —(CH₂)₂— —NH—C(═O)— K200 J009 T152 613 —(CH₂)₂— —NH—C(═O)— K200 J009 T169 614 —(CH₂)₂— —NH—C(═O)— K200 J012 T005 615 —(CH₂)₂— —NH—C(═O)— K200 J012 T148 616 —(CH₂)₂— —NH—C(═O)— K200 J012 T151 617 —(CH₂)₂— —NH—C(═O)— K200 J012 T152 618 —(CH₂)₂— —NH—C(═O)— K200 J012 T169 619 —(CH₂)₂— —NH—C(═O)— K200 J016 T005 620 —(CH₂)₂— —NH—C(═O)— K200 J016 T148 621 —(CH₂)₂— —NH—C(═O)— K200 J016 T169 622 —(CH₂)₂— —NH—C(═O)— K200 J033 T005 623 —(CH₂)₂— —NH—C(═O)— K200 J033 T148 624 —(CH₂)₂— —NH—C(═O)— K200 J033 T152 625 —(CH₂)₂— —NH—C(═O)— K200 J045 T005 626 —(CH₂)₂— —NH—C(═O)— K200 J045 T148 627 —(CH₂)₂— —NH—C(═O)— K200 J045 T151 628 —(CH₂)₂— —NH—C(═O)— K200 J045 T152 629 —(CH₂)₂— —NH—C(═O)— K200 J045 T169 630 —(CH₂)₂— —NH—C(═O)— K200 J050 T148 631 —(CH₂)₂— —NH—C(═O)— K200 J050 T151 632 —(CH₂)₂— —NH—C(═O)— K200 J067 T148 633 —(CH₂)₂— —NH—C(═O)— K200 J067 T169 634 —(CH₂)₂— —NH—C(═O)— K200 J084 T148 635 —(CH₂)₂— —NH—C(═O)— K200 J084 T152 636 —(CH₂)₂— —NH—C(═O)— K201 J008 T134 637 —(CH₂)₂— —NH—C(═O)— K202 J009 T135 638 —(CH₂)₂— —NH—C(═O)— K203 J008 T148 639 —(CH₂)₂— —NH—C(═O)— K203 J009 T148 640 —(CH₂)₂— —NH—C(═O)— K203 J012 T145 641 —(CH₂)₂— —NH—C(═O)— K203 J012 T148 642 —(CH₂)₂— —NH—C(═O)— K203 J017 T148 643 —(CH₂)₂— —NH—C(═O)— K203 J017 T151 644 —(CH₂)₂— —NH—C(═O)— K203 J034 T148 645 —(CH₂)₂— —NH—C(═O)— K203 J034 T169 646 —(CH₂)₂— —NH—C(═O)— K203 J045 T148 647 —(CH₂)₂— —NH—C(═O)— K203 J051 T148 648 —(CH₂)₂— —NH—C(═O)— K203 J051 T152 649 —(CH₂)₂— —NH—C(═O)— K203 J068 T148 650 —(CH₂)₂— —NH—C(═O)— K203 J068 T151 651 —(CH₂)₂— —NH—C(═O)— K203 J085 T148 652 —(CH₂)₂— —NH—C(═O)— K203 J085 T169 653 —(CH₂)₂— —NH—C(═O)— K204 J014 T148 654 —(CH₂)₂— —NH—C(═O)— K205 J015 T149 655 —(CH₂)₂— —NH—C(═O)— K206 J008 T148 656 —(CH₂)₂— —NH—C(═O)— K206 J009 T148 657 —(CH₂)₂— —NH—C(═O)— K206 J012 T148 658 —(CH₂)₂— —NH—C(═O)— K206 J018 T151 659 —(CH₂)₂— —NH—C(═O)— K206 J045 T148 660 —(CH₂)₂— —NH—C(═O)— K207 J008 T148 661 —(CH₂)₂— —NH—C(═O)— K207 J009 T148 662 —(CH₂)₂— —NH—C(═O)— K207 J012 T148 663 —(CH₂)₂— —NH—C(═O)— K207 J043 T152 664 —(CH₂)₂— —NH—C(═O)— K207 J045 T148 665 —(CH₂)₂— —NH—C(═O)— K208 J008 T148 666 —(CH₂)₂— —NH—C(═O)— K208 J009 T148 667 —(CH₂)₂— —NH—C(═O)— K208 J012 T148 668 —(CH₂)₂— —NH—C(═O)— K208 J045 T148 669 —(CH₂)₂— —NH—C(═O)— K208 J045 T157 670 —(CH₂)₂— —NH—C(═O)— K209 J008 T148 671 —(CH₂)₂— —NH—C(═O)— K209 J009 T148 672 —(CH₂)₂— —NH—C(═O)— K209 J012 T148 673 —(CH₂)₂— —NH—C(═O)— K209 J045 T148 674 —(CH₂)₂— —NH—C(═O)— K209 J063 T158 675 —(CH₂)₂— —NH—C(═O)— K210 J008 T148 676 —(CH₂)₂— —NH—C(═O)— K210 J009 T148 677 —(CH₂)₂— —NH—C(═O)— K270 J012 T148 678 —(CH₂)₂— —NH—C(═O)— K210 J045 T148 679 —(CH₂)₂— —NH—C(═O)— K210 J081 T164 680 —(CH₂)₂— —NH—C(═O)— K211 J001 T168 681 —(CH₂)₂— —NH—C(═O)— K211 J008 T148 682 —(CH₂)₂— —NH—C(═O)— K211 J009 T148 683 —(CH₂)₂— —NH—C(═O)— K211 J012 T148 684 —(CH₂)₂— —NH—C(═O)— K211 J045 T148 685 —(CH₂)₂— —NH—C(═O)— K212 J002 T169 686 —(CH₂)₂— —NH—C(═O)— K212 J008 T148 687 —(CH₂)₂— —NH—C(═O)— K212 J009 T148 688 —(CH₂)₂— —NH—C(═O)— K212 J012 T148 689 —(CH₂)₂— —NH—C(═O)— K212 J045 T148 690 —(CH₂)₂— —NH—C(═O)— K213 J008 T170 691 —(CH₂)₂— —NH—C(═O)— K214 J009 T173 692 —(CH₂)₂— —NH—C(═O)— K215 J008 T148 693 —(CH₂)₂— —NH—C(═O)— K215 J009 T148 694 —(CH₂)₂— —NH—C(═O)— K215 J012 T148 695 —(CH₂)₂— —NH—C(═O)— K215 J012 T176 696 —(CH₂)₂— —NH—C(═O)— K215 J045 T148 697 —(CH₂)₂— —NH—C(═O)— K216 J014 T178 698 —(CH₂)₂— —NH—C(═O)— K217 J015 T129 699 —(CH₂)₂— —NH—C(═O)— K218 J018 T130 700 —(CH₂)₂— —NH—C(═O)— K219 J008 T148 701 —(CH₂)₂— —NH—C(═O)— K219 J009 T148 702 —(CH₂)₂— —NH—C(═O)— K219 J012 T148 703 —(CH₂)₂— —NH—C(═O)— K219 J043 T134 704 —(CH₂)₂— —NH—C(═O)— K219 J045 T148 705 —(CH₂)₂— —NH—C(═O)— K220 J008 T148 706 —(CH₂)₂— —NH—C(═O)— K220 J009 T148 707 —(CH₂)₂— —NH—C(═O)— K220 J012 T148 708 —(CH₂)₂— —NH—C(═O)— K220 J045 T135 709 —(CH₂)₂— —NH—C(═O)— K220 J045 T148 710 —(CH₂)₂— —NH—C(═O)— K221 J008 T148 711 —(CH₂)₂— —NH—C(═O)— K221 J009 T148 712 —(CH₂)₂— —NH—C(═O)— K221 J012 T148 713 —(CH₂)₂— —NH—C(═O)— K221 J045 T148 714 —(CH₂)₂— —NH—C(═O)— K221 J063 T145 715 —(CH₂)₂— —NH—C(═O)— K222 J008 T148 716 —(CH₂)₂— —NH—C(═O)— K222 J009 T148 717 —(CH₂)₂— —NH—C(═O)— K222 J012 T148 718 —(CH₂)₂— —NH—C(═O)— K222 J045 T148 719 —(CH₂)₂— —NH—C(═O)— K222 J081 T148 720 —(CH₂)₂— —NH—C(═O)— K223 J001 T149 721 —(CH₂)₂— —NH—C(═O)— K223 J008 T148 722 —(CH₂)₂— —NH—C(═O)— K223 J009 T148 723 —(CH₂)₂— —NH—C(═O)— K223 J012 T148 724 —(CH₂)₂— —NH—C(═O)— K223 J045 T148 725 —(CH₂)₂— —NH—C(═O)— K224 J002 T151 726 —(CH₂)₂— —NH—C(═O)— K224 J008 T148 727 —(CH₂)₂— —NH—C(═O)— K224 J009 T148 728 —(CH₂)₂— —NH—C(═O)— K224 J012 T148 729 —(CH₂)₂— —NH—C(═O)— K224 J045 T148 730 —(CH₂)₂— —NH—C(═O)— K225 J008 T148 731 —(CH₂)₂— —NH—C(═O)— K225 J008 T152 732 —(CH₂)₂— —NH—C(═O)— K225 J009 T148 733 —(CH₂)₂— —NH—C(═O)— K225 J012 T148 734 —(CH₂)₂— —NH—C(═O)— K225 J045 T148 735 —(CH₂)₂— —NH—C(═O)— K226 J009 T157 736 —(CH₂)₂— —NH—C(═O)— K227 J012 T158 737 —(CH₂)₂— —NH—C(═O)— K228 J008 T148 738 —(CH₂)₂— —NH—C(═O)— K228 J009 T148 739 —(CH₂)₂— —NH—C(═O)— K228 J012 T148 740 —(CH₂)₂— —NH—C(═O)— K228 J014 T164 741 —(CH₂)₂— —NH—C(═O)— K228 J045 T148 742 —(CH₂)₂— —NH—C(═O)— K229 J015 T168 743 —(CH₂)₂— —NH—C(═O)— K230 J018 T169 744 —(CH₂)₂— —NH—C(═O)— K231 J043 T170 745 —(CH₂)₂— —NH—C(═O)— K232 J045 T173 746 —(CH₂)₂— —NH—C(═O)— K233 J063 T176 747 —(CH₂)₂— —NH—C(═O)— K234 J081 T178 748 —(CH₂)₂— —NH—C(═O)— K235 J012 T148 749 —(CH₂)₂— —NH—C(═O)— K236 J045 T148 750 —(CH₂)₂— —NH—C(═O)—NH— K003 J002 T148 751 —(CH₂)₂— —NH—C(═O)—NH— K003 J002 T151 752 —(CH₂)₂— —NH—C(═O)—NH— K003 J008 T148 753 —(CH₂)₂— —NH—C(═O)—NH— K003 J008 T151 754 —(CH₂)₂— —NH—C(═O)—NH— K003 J008 T152 755 —(CH₂)₂— —NH—C(═O)—NH— K003 J008 T169 756 —(CH₂)₂— —NH—C(═O)—NH— K003 J009 T148 757 —(CH₂)₂— —NH—C(═O)—NH— K003 J009 T151 758 —(CH₂)₂— —NH—C(═O)—NH— K003 J009 T152 759 —(CH₂)₂— —NH—C(═O)—NH— K003 J009 T169 760 —(CH₂)₂— —NH—C(═O)—NH— K003 J012 T148 761 —(CH₂)₂— —NH—C(═O)—NH— K003 J012 T151 762 —(CH₂)₂— —NH—C(═O)—NH— K003 J012 T152 763 —(CH₂)₂— —NH—C(═O)—NH— K003 J012 T169 764 —(CH₂)₂— —NH—C(═O)—NH— K003 J019 T148 765 —(CH₂)₂— —NH—C(═O)—NH— K003 J019 T169 766 —(CH₂)₂— —NH—C(═O)—NH— K003 J036 T148 767 —(CH₂)₂— —NH—C(═O)—NH— K003 J036 T152 768 —(CH₂)₂— —NH—C(═O)—NH— K003 J045 T148 769 —(CH₂)₂— —NH—C(═O)—NH— K003 J045 T151 770 —(CH₂)₂— —NH—C(═O)—NH— K003 J045 T152 771 —(CH₂)₂— —NH—C(═O)—NH— K003 J045 T169 772 —(CH₂)₂— —NH—C(═O)—NH— K003 J053 T148 773 —(CH₂)₂— —NH—C(═O)—NH— K003 J053 T151 774 —(CH₂)₂— —NH—C(═O)—NH— K003 J070 T148 775 —(CH₂)₂— —NH—C(═O)—NH— K003 J070 T169 776 —(CH₂)₂— —NH—C(═O)—NH— K009 J045 T148 777 —(CH₂)₂— —NH—C(═O)—NH— K012 J008 T148 778 —(CH₂)₂— —NH—C(═O)—NH— K012 J008 T151 779 —(CH₂)₂— —NH—C(═O)—NH— K012 J008 T152 780 —(CH₂)₂— —NH—C(═O)—NH— K012 J008 T169 781 —(CH₂)₂— —NH—C(═O)—NH— K012 J009 T148 782 —(CH₂)₂— —NH—C(═O)—NH— K012 J009 T151 783 —(CH₂)₂— —NH—C(═O)—NH— K012 J009 T152 784 —(CH₂)₂— —NH—C(═O)—NH— K012 J009 T169 785 —(CH₂)₂— —NH—C(═O)—NH— K012 J012 T148 786 —(CH₂)₂— —NH—C(═O)—NH— K012 J012 T151 787 —(CH₂)₂— —NH—C(═O)—NH— K012 J012 T152 788 —(CH₂)₂— —NH—C(═O)—NH— K012 J012 T169 789 —(CH₂)₂— —NH—C(═O)—NH— K012 J026 T148 790 —(CH₂)₂— —NH—C(═O)—NH— K012 J026 T151 791 —(CH₂)₂— —NH—C(═O)—NH— K012 J043 T148 792 —(CH₂)₂— —NH—C(═O)—NH— K012 J043 T169 793 —(CH₂)₂— —NH—C(═O)—NH— K012 J045 T148 794 —(CH₂)₂— —NH—C(═O)—NH— K012 J045 T151 795 —(CH₂)₂— —NH—C(═O)—NH— K012 J045 T152 796 —(CH₂)₂— —NH—C(═O)—NH— K012 J045 T169 797 —(CH₂)₂— —NH—C(═O)—NH— K012 J060 T148 798 —(CH₂)₂— —NH—C(═O)—NH— K012 J060 T152 799 —(CH₂)₂— —NH—C(═O)—NH— K012 J077 T148 800 —(CH₂)₂— —NH—C(═O)—NH— K012 J077 T151 801 —(CH₂)₂— —NH—C(═O)—NH— K013 J045 T148 802 —(CH₂)₂— —NH—C(═O)—NH— K014 J045 T148 803 —(CH₂)₂— —NH—C(═O)—NH— K017 J045 T148 804 —(CH₂)₂— —NH—C(═O)—NH— K032 J045 T148 805 —(CH₂)₂— —NH—C(═O)—NH— K229 J045 T148 806 —(CH₂)₂— —NH—C(═O)—NH— K230 J045 T148 807 —(CH₂)₂— —NH—C(═O)—NH— K231 J045 T148 808 —(CH₂)₂— —NH—C(═O)—NH— K232 J045 T148 809 —(CH₂)₂— —NH—C(═O)—NH— K233 J045 T148 810 —(CH₂)₂— —NH—C(═O)—NH— K234 J045 T148 811 —(CH₂)₂— —NH—C(═O)—NH— K235 J045 T148 812 —(CH₂)₂— —NH—C(═O)—NH— K236 J045 T148 813 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T001 814 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T005 815 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T010 816 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T019 817 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T028 818 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T037 819 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T046 820 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T055 821 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T064 822 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T073 823 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T082 824 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T091 825 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T100 826 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T109 827 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T118 828 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T127 829 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T136 830 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T145 831 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T154 832 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T163 833 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T172 834 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T002 835 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T011 836 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T020 837 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T029 838 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T038 839 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T047 840 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T056 841 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T065 842 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T074 843 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T083 844 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T092 845 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T101 846 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T110 847 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T119 848 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T128 849 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T137 850 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T146 851 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T155 852 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T164 853 —(CH₂)₂— —NH—C(═O)—O— K005 J002 T173 854 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T003 855 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T005 856 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T012 857 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T021 858 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T030 859 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T039 860 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T048 861 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T057 862 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T066 863 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T075 864 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T084 865 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T093 866 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T102 867 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T111 868 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T120 869 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T129 870 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T138 871 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T147 872 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T156 873 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T165 874 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T174 875 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T004 876 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T005 877 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T013 878 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T022 879 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T031 880 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T040 881 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T049 882 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T058 883 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T067 884 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T076 885 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T085 886 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T094 887 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T103 888 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T112 889 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T121 890 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T130 891 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T139 892 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T148 893 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T157 894 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T166 895 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T175 896 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T005 897 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T014 898 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T017 899 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T023 900 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T032 901 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T041 902 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T050 903 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T055 904 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T059 905 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T068 906 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T077 907 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T086 908 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T095 909 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T104 910 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T113 911 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T122 912 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T129 913 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T131 914 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T140 915 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T148 916 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T149 917 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T151 918 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T152 919 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T158 920 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T167 921 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T176 922 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T005 923 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T006 924 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T015 925 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T024 926 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T033 927 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T042 928 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T051 929 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T060 930 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T069 931 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T078 932 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T087 933 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T096 934 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T105 935 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T114 936 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T123 937 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T132 938 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T141 939 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T150 940 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T159 941 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T168 942 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T177 943 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T001 944 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T003 945 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T004 946 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T005 947 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T007 948 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T008 949 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T016 950 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T017 951 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T018 952 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T019 953 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T020 954 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T025 955 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T034 956 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T042 957 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T043 958 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T052 959 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T055 960 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T061 961 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T070 962 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T077 963 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T079 964 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T088 965 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T090 966 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T096 967 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T097 968 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T100 969 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T106 970 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T108 971 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T110 972 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T111 973 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T114 974 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T115 975 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T116 976 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T118 977 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T119 978 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T121 979 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T122 980 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T123 981 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T124 982 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T128 983 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T129 984 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T130 985 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T133 986 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T136 987 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T137 988 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T138 989 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T139 990 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T140 991 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T141 992 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T142 993 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T143 994 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T144 995 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T145 996 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T146 997 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T147 998 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T148 999 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T149 1000 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T150 1001 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T151 1002 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T152 1003 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T153 1004 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T154 1005 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T155 1006 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T156 1007 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T157 1008 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T158 1009 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T159 1010 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T160 1011 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T162 1012 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T163 1013 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T167 1014 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T169 1015 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T178 1016 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T008 1017 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T017 1018 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T026 1019 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T035 1020 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T044 1021 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T053 1022 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T062 1023 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T071 1024 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T080 1025 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T089 1026 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T098 1027 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T107 1028 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T116 1029 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T125 1030 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T134 1031 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T143 1032 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T152 1033 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T161 1034 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T170 1035 —(CH₂)₂— —NH—C(═O)—O— K005 J063 T179 1036 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T009 1037 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T018 1038 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T027 1039 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T036 1040 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T045 1041 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T054 1042 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T063 1043 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T072 1044 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T081 1045 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T090 1046 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T099 1047 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T108 1048 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T117 1049 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T126 1050 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T135 1051 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T144 1052 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T153 1053 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T162 1054 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T171 1055 —(CH₂)₂— Single bond K179 J012 T148 1056 —(CH₂)₂— Single bond K180 J045 T148 1057 —(CH₂)₂— Single bond K239 J045 T148 1058 —(CH₂)₃— —C(═O)— K002 J001 T151 1059 —(CH₂)₃— —C(═O)— K002 J012 T151 1060 —(CH₂)₃— —C(═O)— K003 J001 T151 1061 —(CH₂)₃— —C(═O)— K003 J012 T151 1062 —(CH₂)₃— —C(═O)— K004 J001 T151 1063 —(CH₂)₃— —C(═O)— K004 J012 T151 1064 —(CH₂)₃— —C(═O)— K005 J001 T151 1065 —(CH₂)₃— —C(═O)— K005 J012 T151 1066 —(CH₂)₃— —C(═O)— K007 J001 T152 1067 —(CH₂)₃— —C(═O)— K007 J012 T152 1068 —(CH₂)₃— —C(═O)— K008 J001 T152 1069 —(CH₂)₃— —C(═O)— K008 J012 T152 1070 —(CH₂)₃— —C(═O)— K009 J001 T152 1071 —(CH₂)₃— —C(═O)— K009 J012 T152 1072 —(CH₂)₃— —C(═O)— K012 J001 T152 1073 —(CH₂)₃— —C(═O)— K012 J012 T152 1074 —(CH₂)₃— —C(═O)— K107 J001 T168 1075 —(CH₂)₃— —C(═O)— K107 J012 T169 1076 —(CH₂)₃— —C(═O)— K108 J001 T169 1077 —(CH₂)₃— —C(═O)— K108 J012 T169 1078 —(CH₂)₃— —C(═O)— K112 J001 T170 1079 —(CH₂)₃— —C(═O)— K112 J012 T169 1080 —(CH₂)₃— —C(═O)— K129 J001 T171 1081 —(CH₂)₃— —C(═O)— K129 J012 T169 1082 —(CH₂)₃— —C(═O)— K133 J001 T172 1083 —(CH₂)₃— —C(═O)— K133 J012 T169 1084 —(CH₂)₃— —C(═O)— K137 J001 T173 1085 —(CH₂)₃— —C(═O)— K137 J012 T169 1086 —(CH₂)₃— —C(═O)—O— K001 J001 T148 1087 —(CH₂)₃— —C(═O)—O— K002 J001 T151 1088 —(CH₂)₃— —C(═O)—O— K193 J001 T152 1089 —(CH₂)₃— —C(═O)—O— K227 J001 T169 1090 —(CH₂)₃— —NH— K185 J045 T151 1091 —(CH₂)₃— —NH— K185 J045 T169 1092 —(CH₂)₃— —NH—C(═O)— K008 J012 T151 1093 —(CH₂)₃— —NH—C(═O)— K008 J012 T169 1094 —(CH₂)₃— —NH—C(═O)— K013 J001 T151 1095 —(CH₂)₃— —NH—C(═O)— K013 J001 T169 1096 —(CH₂)₃— —NH—C(═O)— K200 J045 T148 1097 —(CH₂)₃— —NH—C(═O)— K200 J045 T152 1098 —(CH₂)₃— —NH—C(═O)—NH— K003 J012 T148 1099 —(CH₂)₃— —NH—C(═O)—NH— K003 J012 T152 1100 —(CH₂)₃— —NH—C(═O)—O— K005 J001 T148 1101 —(CH₂)₃— —NH—C(═O)—O— K005 J001 T152 1102 —CH₂— —C(═O)— K107 J001 T148 1103 —CH₂— —C(═O)— K107 J012 T148 1104 —CH₂— —C(═O)— K107 J018 T148 1105 —CH₂— —C(═O)— K108 J001 T129 1106 —CH₂— —C(═O)— K108 J001 T148 1107 —CH₂— —C(═O)— K108 J001 T151 1108 —CH₂— —C(═O)— K108 J001 T152 1109 —CH₂— —C(═O)— K108 J001 T164 1110 —CH₂— —C(═O)— K108 J001 T170 1111 —CH₂— —C(═O)— K108 J001 T171 1112 —CH₂— —C(═O)— K108 J012 T148 1113 —CH₂— —C(═O)— K108 J022 T148 1114 —CH₂— —C(═O)— K112 J001 T148 1115 —CH₂— —C(═O)— K112 J012 T148 1116 —CH₂— —C(═O)— K129 J001 T148 1117 —CH₂— —C(═O)— K129 J012 T148 1118 —CH₂— —C(═O)— K129 J014 T148 1119 —CH₂— —C(═O)— K133 J001 T148 1120 —CH₂— —C(═O)— K133 J008 T148 1121 —CH₂— —C(═O)— K133 J012 T148 1122 —CH₂— —C(═O)— K137 J001 T129 1123 —CH₂— —C(═O)— K137 J001 T148 1124 —CH₂— —C(═O)— K137 J001 T151 1125 —CH₂— —C(═O)— K137 J001 T152 1126 —CH₂— —C(═O)— K137 J001 T164 1127 —CH₂— —C(═O)— K137 J001 T170 1128 —CH₂— —C(═O)— K137 J001 T172 1129 —CH₂— —C(═O)— K137 J009 T148 1130 —CH₂— —C(═O)— K137 J012 T148 1131 —CH₂— —C(═O)— K237 J001 T148 1132 —CH₂— —C(═O)—NH— K001 J001 T148 1133 —CH₂— —C(═O)—NH— K002 J001 T148 1134 —CH₂— —C(═O)—NH— K002 J012 T148 1135 —CH₂— —C(═O)—NH— K002 J063 T148 1136 —CH₂— —C(═O)—NH— K003 J001 T148 1137 —CH₂— —C(═O)—NH— K003 J012 T148 1138 —CH₂— —C(═O)—NH— K003 J065 T148 1139 —CH₂— —C(═O)—NH— K004 J001 T148 1140 —CH₂— —C(═O)—NH— K004 J012 T148 1141 —CH₂— —C(═O)—NH— K004 J070 T148 1142 —CH₂— —C(═O)—NH— K005 J001 T148 1143 —CH₂— —C(═O)—NH— K005 J012 T148 1144 —CH₂— —C(═O)—NH— K005 J075 T148 1145 —CH₂— —C(═O)—NH— K007 J001 T129 1146 —CH₂— —C(═O)—NH— K007 J001 T148 1147 —CH₂— —C(═O)—NH— K007 J001 T151 1148 —CH₂— —C(═O)—NH— K007 J001 T152 1149 —CH₂— —C(═O)—NH— K007 J001 T164 1150 —CH₂— —C(═O)—NH— K007 J001 T169 1151 —CH₂— —C(═O)—NH— K007 J001 T170 1152 —CH₂— —C(═O)—NH— K007 J012 T148 1153 —CH₂— —C(═O)—NH— K007 J081 T148 1154 —CH₂— —C(═O)—NH— K008 J001 T148 1155 —CH₂— —C(═O)—NH— K008 J012 T148 1156 —CH₂— —C(═O)—NH— K008 J085 T148 1157 —CH₂— —C(═O)—NH— K009 J001 T148 1158 —CH₂— —C(═O)—NH— K009 J012 T148 1159 —CH₂— —C(═O)—NH— K009 J043 T148 1160 —CH₂— —C(═O)—NH— K012 J001 T129 1161 —CH₂— —C(═O)—NH— K012 J001 T148 1162 —CH₂— —C(═O)—NH— K012 J001 T151 1163 —CH₂— —C(═O)—NH— K012 J001 T152 1164 —CH₂— —C(═O)—NH— K012 J001 T164 1165 —CH₂— —C(═O)—NH— K012 J001 T170 1166 —CH₂— —C(═O)—NH— K012 J012 T148 1167 —CH₂— —C(═O)—NH— K012 J045 T148 1168 —CH₂— —C(═O)—NH— K218 J001 T148 1169 —CH₂— —C(═O)—O— K001 J001 T148 1170 —CH₂— —C(═O)—O— K002 J001 T148 1171 —CH₂— —C(═O)—O— K002 J001 T151 1172 —CH₂— —C(═O)—O— K193 J001 T152 1173 —CH₂— —C(═O)—O— K227 J001 T169 1174 Single bond Single bond K001 J001 T148 1175 Single bond Single bond K001 J002 T148 1176 Single bond Single bond K197 J001 T005 1177 Single bond Single bond K197 J001 T148 1178 Single bond Single bond K197 J012 T148 1179 Single bond Single bond K223 J001 T148 1180 Single bond Single bond K223 J002 T148 1181 —(CH₂)₂— —NH— K078 J001 T148 1182 —(CH₂)₂— —NH— K078 J045 T148 1183 —(CH₂)₂— —NH— K078 J045 T170 1184 —(CH₂)₂— —NH— K182 J001 T148 1185 —(CH₂)₂— —NH— K372 J045 T148 1186 —(CH₂)₂— —NH— K392 J045 T170 1187 —(CH₂)₂— —NH—C(═O)— K003 J044 T170 1188 —(CH₂)₂— —NH—C(═O)— K004 J007 T148 1189 —(CH₂)₂— —NH—C(═O)— K004 J010 T148 1190 —(CH₂)₂— —NH—C(═O)— K004 J013 T148 1191 —(CH₂)₂— —NH—C(═O)— K004 J014 T148 1192 —(CH₂)₂— —NH—C(═O)— K004 J044 T148 1193 —(CH₂)₂— —NH—C(═O)— K004 J044 T170 1194 —(CH₂)₂— —NH—C(═O)— K006 J007 T148 1195 —(CH₂)₂— —NH—C(═O)— K006 J010 T148 1196 —(CH₂)₂— —NH—C(═O)— K006 J013 T148 1197 —(CH₂)₂— —NH—C(═O)— K007 J007 T148 1198 —(CH₂)₂— —NH—C(═O)— K007 J010 T148 1199 —(CH₂)₂— —NH—C(═O)— K007 J013 T148 1200 —(CH₂)₂— —NH—C(═O)— K007 J014 T148 1201 —(CH₂)₂— —NH—C(═O)— K007 J039 T170 1202 —(CH₂)₂— —NH—C(═O)— K007 J044 T148 1203 —(CH₂)₂— —NH—C(═O)— K007 J044 T169 1204 —(CH₂)₂— —NH—C(═O)— K007 J044 T170 1205 —(CH₂)₂— —NH—C(═O)— K007 J045 T151 1206 —(CH₂)₂— —NH—C(═O)— K007 J045 T170 1207 —(CH₂)₂— —NH—C(═O)— K008 J007 T148 1208 —(CH₂)₂— —NH—C(═O)— K008 J010 T148 1209 —(CH₂)₂— —NH—C(═O)— K008 J013 T148 1210 —(CH₂)₂— —NH—C(═O)— K008 J014 T148 1211 —(CH₂)₂— —NH—C(═O)— K008 J039 T170 1212 —(CH₂)₂— —NH—C(═O)— K008 J044 T148 1213 —(CH₂)₂— —NH—C(═O)— K008 J044 T169 1214 —(CH₂)₂— —NH—C(═O)— K008 J044 T170 1215 —(CH₂)₂— —NH—C(═O)— K008 J045 T151 1216 —(CH₂)₂— —NH—C(═O)— K008 J045 T169 1217 —(CH₂)₂— —NH—C(═O)— K008 J045 T170 1218 —(CH₂)₂— —NH—C(═O)— K009 J007 T148 1219 —(CH₂)₂— —NH—C(═O)— K009 J010 T148 1220 —(CH₂)₂— —NH—C(═O)— K009 J013 T148 1221 —(CH₂)₂— —NH—C(═O)— K009 J014 T148 1222 —(CH₂)₂— —NH—C(═O)— K009 J037 T170 1223 —(CH₂)₂— —NH—C(═O)— K009 J039 T170 1224 —(CH₂)₂— —NH—C(═O)— K009 J043 T170 1225 —(CH₂)₂— —NH—C(═O)— K009 J044 T148 1226 —(CH₂)₂— —NH—C(═O)— K009 J044 T170 1227 —(CH₂)₂— —NH—C(═O)— K009 J045 T152 1228 —(CH₂)₂— —NH—C(═O)— K009 J045 T170 1229 —(CH₂)₂— —NH—C(═O)— K009 J047 T170 1230 —(CH₂)₂— —NH—C(═O)— K009 J145 T148 1231 —(CH₂)₂— —NH—C(═O)— K009 J147 T148 1232 —(CH₂)₂— —NH—C(═O)— K010 J012 T148 1233 —(CH₂)₂— —NH—C(═O)— K010 J012 T164 1234 —(CH₂)₂— —NH—C(═O)— K010 J013 T148 1235 —(CH₂)₂— —NH—C(═O)— K010 J013 T170 1236 —(CH₂)₂— —NH—C(═O)— K010 J045 T148 1237 —(CH₂)₂— —NH—C(═O)— K010 J045 T170 1238 —(CH₂)₂— —NH—C(═O)— K010 J045 T178 1239 —(CH₂)₂— —NH—C(═O)— K010 J045 T179 1240 —(CH₂)₂— —NH—C(═O)— K011 J044 T170 1241 —(CH₂)₂— —NH—C(═O)— K023 J045 T170 1242 —(CH₂)₂— —NH—C(═O)— K033 J045 T170 1243 —(CH₂)₂— —NH—C(═O)— K104 J045 T170 1244 —(CH₂)₂— —NH—C(═O)— K198 J007 T148 1245 —(CH₂)₂— —NH—C(═O)— K198 J010 T148 1246 —(CH₂)₂— —NH—C(═O)— K198 J013 T148 1247 —(CH₂)₂— —NH—C(═O)— K198 J014 T148 1248 —(CH₂)₂— —NH—C(═O)— K198 J039 T170 1249 —(CH₂)₂— —NH—C(═O)— K198 J044 T170 1250 —(CH₂)₂— —NH—C(═O)— K198 J045 T170 1251 —(CH₂)₂— —NH—C(═O)— K199 J007 T148 1252 —(CH₂)₂— —NH—C(═O)— K199 J010 T148 1253 —(CH₂)₂— —NH—C(═O)— K199 J013 T148 1254 —(CH₂)₂— —NH—C(═O)— K199 J014 T148 1255 —(CH₂)₂— —NH—C(═O)— K199 J039 T170 1256 —(CH₂)₂— —NH—C(═O)— K199 J044 T170 1257 —(CH₂)₂— —NH—C(═O)— K199 J045 T170 1258 —(CH₂)₂— —NH—C(═O)— K200 J001 T170 1259 —(CH₂)₂— —NH—C(═O)— K200 J002 T170 1260 —(CH₂)₂— —NH—C(═O)— K200 J007 T148 1261 —(CH₂)₂— —NH—C(═O)— K200 J007 T170 1262 —(CH₂)₂— —NH—C(═O)— K200 J008 T170 1263 —(CH₂)₂— —NH—C(═O)— K200 J009 T164 1264 —(CH₂)₂— —NH—C(═O)— K200 J009 T170 1265 —(CH₂)₂— —NH—C(═O)— K200 J010 T148 1266 —(CH₂)₂— —NH—C(═O)— K200 J010 T170 1267 —(CH₂)₂— —NH—C(═O)— K200 J011 T148 1268 —(CH₂)₂— —NH—C(═O)— K200 J011 T164 1269 —(CH₂)₂— —NH—C(═O)— K200 J011 T170 1270 —(CH₂)₂— —NH—C(═O)— K200 J012 T164 1271 —(CH₂)₂— —NH—C(═O)— K200 J012 T170 1272 —(CH₂)₂— —NH—C(═O)— K200 J013 T148 1273 —(CH₂)₂— —NH—C(═O)— K200 J013 T170 1274 —(CH₂)₂— —NH—C(═O)— K200 J014 T148 1275 —(CH₂)₂— —NH—C(═O)— K200 J037 T148 1276 —(CH₂)₂— —NH—C(═O)— K200 J037 T169 1277 —(CH₂)₂— —NH—C(═O)— K200 J037 T170 1278 —(CH₂)₂— —NH—C(═O)— K200 J038 T170 1279 —(CH₂)₂— —NH—C(═O)— K200 J039 T148 1280 —(CH₂)₂— —NH—C(═O)— K200 J039 T164 1281 —(CH₂)₂— —NH—C(═O)— K200 J039 T170 1282 —(CH₂)₂— —NH—C(═O)— K200 J043 T148 1283 —(CH₂)₂— —NH—C(═O)— K200 J043 T169 1284 —(CH₂)₂— —NH—C(═O)— K200 J043 T170 1285 —(CH₂)₂— —NH—C(═O)— K200 J044 T148 1286 —(CH₂)₂— —NH—C(═O)— K200 J044 T170 1287 —(CH₂)₂— —NH—C(═O)— K200 J045 T164 1288 —(CH₂)₂— —NH—C(═O)— K200 J045 T170 1289 —(CH₂)₂— —NH—C(═O)— K200 J045 T171 1290 —(CH₂)₂— —NH—C(═O)— K200 J045 T177 1291 —(CH₂)₂— —NH—C(═O)— K200 J045 T178 1292 —(CH₂)₂— —NH—C(═O)— K200 J045 T179 1293 —(CH₂)₂— —NH—C(═O)— K200 J045 T180 1294 —(CH₂)₂— —NH—C(═O)— K200 J047 T148 1295 —(CH₂)₂— —NH—C(═O)— K200 J047 T169 1296 —(CH₂)₂— —NH—C(═O)— K200 J047 T170 1297 —(CH₂)₂— —NH—C(═O)— K200 J079 T148 1298 —(CH₂)₂— —NH—C(═O)— K200 J079 T169 1299 —(CH₂)₂— —NH—C(═O)— K200 J079 T170 1300 —(CH₂)₂— —NH—C(═O)— K200 J080 T148 1301 —(CH₂)₂— —NH—C(═O)— K200 J080 T169 1302 —(CH₂)₂— —NH—C(═O)— K200 J080 T170 1303 —(CH₂)₂— —NH—C(═O)— K200 J081 T148 1304 —(CH₂)₂— —NH—C(═O)— K200 J081 T164 1305 —(CH₂)₂— —NH—C(═O)— K200 J081 T170 1306 —(CH₂)₂— —NH—C(═O)— K200 J082 T148 1307 —(CH₂)₂— —NH—C(═O)— K200 J082 T169 1308 —(CH₂)₂— —NH—C(═O)— K200 J082 T170 1309 —(CH₂)₂— —NH—C(═O)— K200 J090 T148 1310 —(CH₂)₂— —NH—C(═O)— K200 J090 T169 1311 —(CH₂)₂— —NH—C(═O)— K200 J090 T170 1312 —(CH₂)₂— —NH—C(═O)— K200 J092 T148 1313 —(CH₂)₂— —NH—C(═O)— K200 J092 T164 1314 —(CH₂)₂— —NH—C(═O)— K200 J092 T170 1315 —(CH₂)₂— —NH—C(═O)— K200 J093 T148 1316 —(CH₂)₂— —NH—C(═O)— K200 J103 T148 1317 —(CH₂)₂— —NH—C(═O)— K200 J103 T164 1318 —(CH₂)₂— —NH—C(═O)— K200 J103 T170 1319 —(CH₂)₂— —NH—C(═O)— K200 J104 T148 1320 —(CH₂)₂— —NH—C(═O)— K200 J104 T164 1321 —(CH₂)₂— —NH—C(═O)— K200 J104 T170 1322 —(CH₂)₂— —NH—C(═O)— K200 J105 T148 1323 —(CH₂)₂— —NH—C(═O)— K200 J105 T164 1324 —(CH₂)₂— —NH—C(═O)— K200 J105 T169 1325 —(CH₂)₂— —NH—C(═O)— K200 J106 T148 1326 —(CH₂)₂— —NH—C(═O)— K200 J106 T164 1327 —(CH₂)₂— —NH—C(═O)— K200 J106 T170 1328 —(CH₂)₂— —NH—C(═O)— K200 J107 T148 1329 —(CH₂)₂— —NH—C(═O)— K200 J107 T164 1330 —(CH₂)₂— —NH—C(═O)— K200 J107 T170 1331 —(CH₂)₂— —NH—C(═O)— K200 J109 T170 1332 —(CH₂)₂— —NH—C(═O)— K200 J118 T170 1333 —(CH₂)₂— —NH—C(═O)— K200 J138 T170 1334 —(CH₂)₂— —NH—C(═O)— K200 J139 T170 1335 —(CH₂)₂— —NH—C(═O)— K200 J144 T148 1336 —(CH₂)₂— —NH—C(═O)— K200 J144 T169 1337 —(CH₂)₂— —NH—C(═O)— K200 J144 T170 1338 —(CH₂)₂— —NH—C(═O)— K200 J145 T170 1339 —(CH₂)₂— —NH—C(═O)— K200 J146 T148 1340 —(CH₂)₂— —NH—C(═O)— K200 J146 T164 1341 —(CH₂)₂— —NH—C(═O)— K200 J105 T170 1342 —(CH₂)₂— —NH—C(═O)— K200 J147 T148 1343 —(CH₂)₂— —NH—C(═O)— K200 J147 T170 1344 —(CH₂)₂— —NH—C(═O)— K200 J148 T148 1345 —(CH₂)₂— —NH—C(═O)— K200 J149 T148 1346 —(CH₂)₂— —NH—C(═O)— K200 J149 T170 1347 —(CH₂)₂— —NH—C(═O)— K200 J150 T148 1348 —(CH₂)₂— —NH—C(═O)— K200 J150 T170 1349 —(CH₂)₂— —NH—C(═O)— K200 J151 T148 1350 —(CH₂)₂— —NH—C(═O)— K200 J151 T170 1351 —(CH₂)₂— —NH—C(═O)— K200 J152 T148 1352 —(CH₂)₂— —NH—C(═O)— K200 J153 T148 1353 —(CH₂)₂— —NH—C(═O)— K200 J154 T148 1354 —(CH₂)₂— —NH—C(═O)— K200 J155 T148 1355 —(CH₂)₂— —NH—C(═O)— K200 J156 T148 1356 —(CH₂)₂— —NH—C(═O)— K200 J157 T148 1357 —(CH₂)₂— —NH—C(═O)— K200 J158 T148 1358 —(CH₂)₂— —NH—C(═O)— K200 J158 T170 1359 —(CH₂)₂— —NH—C(═O)— K200 J159 T148 1360 —(CH₂)₂— —NH—C(═O)— K200 J159 T170 1361 —(CH₂)₂— —NH—C(═O)— K201 J007 T148 1362 —(CH₂)₂— —NH—C(═O)— K201 J008 T148 1363 —(CH₂)₂— —NH—C(═O)— K201 J010 T148 1364 —(CH₂)₂— —NH—C(═O)— K201 J012 T148 1365 —(CH₂)₂— —NH—C(═O)— K201 J013 T148 1366 —(CH₂)₂— —NH—C(═O)— K201 J014 T148 1367 —(CH₂)₂— —NH—C(═O)— K201 J037 T170 1368 —(CH₂)₂— —NH—C(═O)— K201 J039 T170 1369 —(CH₂)₂— —NH—C(═O)— K201 J043 T170 1370 —(CH₂)₂— —NH—C(═O)— K201 J044 T148 1371 —(CH₂)₂— —NH—C(═O)— K201 J044 T170 1372 —(CH₂)₂— —NH—C(═O)— K201 J045 T148 1373 —(CH₂)₂— —NH—C(═O)— K201 J045 T152 1374 —(CH₂)₂— —NH—C(═O)— K201 J045 T170 1375 —(CH₂)₂— —NH—C(═O)— K201 J047 T170 1376 —(CH₂)₂— —NH—C(═O)— K201 J145 T148 1377 —(CH₂)₂— —NH—C(═O)— K201 J147 T148 1378 —(CH₂)₂— —NH—C(═O)— K202 J007 T148 1379 —(CH₂)₂— —NH—C(═O)— K202 J008 T148 1380 —(CH₂)₂— —NH—C(═O)— K202 J010 T148 1381 —(CH₂)₂— —NH—C(═O)— K202 J012 T148 1382 —(CH₂)₂— —NH—C(═O)— K202 J013 T148 1383 —(CH₂)₂— —NH—C(═O)— K202 J014 T148 1384 —(CH₂)₂— —NH—C(═O)— K202 J039 T170 1385 —(CH₂)₂— —NH—C(═O)— K202 J044 T148 1386 —(CH₂)₂— —NH—C(═O)— K202 J044 T164 1387 —(CH₂)₂— —NH—C(═O)— K202 J044 T170 1388 —(CH₂)₂— —NH—C(═O)— K202 J045 T148 1389 —(CH₂)₂— —NH—C(═O)— K202 J045 T164 1390 —(CH₂)₂— —NH—C(═O)— K203 J007 T148 1391 —(CH₂)₂— —NH—C(═O)— K203 J010 T148 1392 —(CH₂)₂— —NH—C(═O)— K203 J013 T148 1393 —(CH₂)₂— —NH—C(═O)— K203 J014 T148 1394 —(CH₂)₂— —NH—C(═O)— K203 J039 T170 1395 —(CH₂)₂— —NH—C(═O)— K203 J044 T148 1396 —(CH₂)₂— —NH—C(═O)— K203 J044 T164 1397 —(CH₂)₂— —NH—C(═O)— K203 J044 T170 1398 —(CH₂)₂— —NH—C(═O)— K203 J045 T164 1399 —(CH₂)₂— —NH—C(═O)— K203 J045 T170 1400 —(CH₂)₂— —NH—C(═O)— K204 J007 T148 1401 —(CH₂)₂— —NH—C(═O)— K204 J008 T148 1402 —(CH₂)₂— —NH—C(═O)— K204 J009 T170 1403 —(CH₂)₂— —NH—C(═O)— K204 J010 T148 1404 —(CH₂)₂— —NH—C(═O)— K204 J011 T170 1405 —(CH₂)₂— —NH—C(═O)— K204 J012 T148 1406 —(CH₂)₂— —NH—C(═O)— K204 J013 T148 1407 —(CH₂)₂— —NH—C(═O)— K204 J037 T170 1408 —(CH₂)₂— —NH—C(═O)— K204 J039 T170 1409 —(CH₂)₂— —NH—C(═O)— K204 J043 T170 1410 —(CH₂)₂— —NH—C(═O)— K204 J044 T148 1411 —(CH₂)₂— —NH—C(═O)— K204 J044 T169 1412 —(CH₂)₂— —NH—C(═O)— K204 J044 T170 1413 —(CH₂)₂— —NH—C(═O)— K204 J045 T148 1414 —(CH₂)₂— —NH—C(═O)— K204 J045 T169 1415 —(CH₂)₂— —NH—C(═O)— K204 J045 T170 1416 —(CH₂)₂— —NH—C(═O)— K204 J047 T170 1417 —(CH₂)₂— —NH—C(═O)— K204 J079 T170 1418 —(CH₂)₂— —NH—C(═O)— K204 J145 T148 1419 —(CH₂)₂— —NH—C(═O)— K204 J147 T148 1420 —(CH₂)₂— —NH—C(═O)— K205 J007 T148 1421 —(CH₂)₂— —NH—C(═O)— K205 J008 T148 1422 —(CH₂)₂— —NH—C(═O)— K205 J010 T148 1423 —(CH₂)₂— —NH—C(═O)— K205 J012 T148 1424 —(CH₂)₂— —NH—C(═O)— K205 J013 T148 1425 —(CH₂)₂— —NH—C(═O)— K205 J014 T148 1426 —(CH₂)₂— —NH—C(═O)— K205 J044 T170 1427 —(CH₂)₂— —NH—C(═O)— K205 J045 T170 1428 —(CH₂)₂— —NH—C(═O)— K206 J039 T170 1429 —(CH₂)₂— —NH—C(═O)— K206 J044 T170 1430 —(CH₂)₂— —NH—C(═O)— K206 J045 T170 1431 —(CH₂)₂— —NH—C(═O)— K207 J044 T170 1432 —(CH₂)₂— —NH—C(═O)— K208 J007 T148 1433 —(CH₂)₂— —NH—C(═O)— K208 J009 T170 1434 —(CH₂)₂— —NH—C(═O)— K208 J010 T148 1435 —(CH₂)₂— —NH—C(═O)— K208 J011 T170 1436 —(CH₂)₂— —NH—C(═O)— K208 J013 T148 1437 —(CH₂)₂— —NH—C(═O)— K208 J014 T148 1438 —(CH₂)₂— —NH—C(═O)— K208 J037 T170 1439 —(CH₂)₂— —NH—C(═O)— K208 J039 T170 1440 —(CH₂)₂— —NH—C(═O)— K208 J043 T170 1441 —(CH₂)₂— —NH—C(═O)— K208 J044 T148 1442 —(CH₂)₂— —NH—C(═O)— K208 J044 T169 1443 —(CH₂)₂— —NH—C(═O)— K208 J044 T170 1444 —(CH₂)₂— —NH—C(═O)— K208 J045 T169 1445 —(CH₂)₂— —NH—C(═O)— K208 J045 T170 1446 —(CH₂)₂— —NH—C(═O)— K208 J047 T170 1447 —(CH₂)₂— —NH—C(═O)— K208 J079 T170 1448 —(CH₂)₂— —NH—C(═O)— K208 J145 T148 1449 —(CH₂)₂— —NH—C(═O)— K208 J147 T148 1450 —(CH₂)₂— —NH—C(═O)— K209 J007 T148 1451 —(CH₂)₂— —NH—C(═O)— K209 J010 T148 1452 —(CH₂)₂— —NH—C(═O)— K209 J013 T148 1453 —(CH₂)₂— —NH—C(═O)— K209 J014 T148 1454 —(CH₂)₂— —NH—C(═O)— K209 J044 T170 1455 —(CH₂)₂— —NH—C(═O)— K210 J007 T148 1456 —(CH₂)₂— —NH—C(═O)— K210 J010 T148 1457 —(CH₂)₂— —NH—C(═O)— K210 J013 T148 1458 —(CH₂)₂— —NH—C(═O)— K210 J014 T148 1459 —(CH₂)₂— —NH—C(═O)— K210 J044 T170 1460 —(CH₂)₂— —NH—C(═O)— K213 J007 T148 1461 —(CH₂)₂— —NH—C(═O)— K213 J008 T148 1462 —(CH₂)₂— —NH—C(═O)— K213 J010 T148 1463 —(CH₂)₂— —NH—C(═O)— K213 J012 T148 1464 —(CH₂)₂— —NH—C(═O)— K213 J013 T148 1465 —(CH₂)₂— —NH—C(═O)— K213 J014 T148 1466 —(CH₂)₂— —NH—C(═O)— K213 J044 T170 1467 —(CH₂)₂— —NH—C(═O)— K214 J007 T148 1468 —(CH₂)₂— —NH—C(═O)— K214 J008 T148 1469 —(CH₂)₂— —NH—C(═O)— K214 J010 T148 1470 —(CH₂)₂— —NH—C(═O)— K214 J012 T148 1471 —(CH₂)₂— —NH—C(═O)— K214 J013 T148 1472 —(CH₂)₂— —NH—C(═O)— K214 J014 T148 1473 —(CH₂)₂— —NH—C(═O)— K214 J044 T170 1474 —(CH₂)₂— —NH—C(═O)— K215 J007 T148 1475 —(CH₂)₂— —NH—C(═O)— K215 J010 T148 1476 —(CH₂)₂— —NH—C(═O)— K215 J013 T148 1477 —(CH₂)₂— —NH—C(═O)— K215 J014 T148 1478 —(CH₂)₂— —NH—C(═O)— K215 J044 T170 1479 —(CH₂)₂— —NH—C(═O)— K216 J007 T148 1480 —(CH₂)₂— —NH—C(═O)— K216 J008 T148 1481 —(CH₂)₂— —NH—C(═O)— K216 J010 T148 1482 —(CH₂)₂— —NH—C(═O)— K216 J012 T148 1483 —(CH₂)₂— —NH—C(═O)— K216 J013 T148 1484 —(CH₂)₂— —NH—C(═O)— K216 J014 T148 1485 —(CH₂)₂— —NH—C(═O)— K216 J044 T170 1486 —(CH₂)₂— —NH—C(═O)— K216 J045 T170 1487 —(CH₂)₂— —NH—C(═O)— K217 J007 T148 1488 —(CH₂)₂— —NH—C(═O)— K217 J008 T148 1489 —(CH₂)₂— —NH—C(═O)— K217 J010 T148 1490 —(CH₂)₂— —NH—C(═O)— K217 J012 T148 1491 —(CH₂)₂— —NH—C(═O)— K217 J013 T148 1492 —(CH₂)₂— —NH—C(═O)— K217 J014 T148 1493 —(CH₂)₂— —NH—C(═O)— K217 J044 T170 1494 —(CH₂)₂— —NH—C(═O)— K217 J045 T170 1495 —(CH₂)₂— —NH—C(═O)— K218 J007 T148 1496 —(CH₂)₂— —NH—C(═O)— K218 J008 T148 1497 —(CH₂)₂— —NH—C(═O)— K218 J010 T148 1498 —(CH₂)₂— —NH—C(═O)— K218 J012 T148 1499 —(CH₂)₂— —NH—C(═O)— K218 J012 T164 1500 —(CH₂)₂— —NH—C(═O)— K218 J013 T148 1501 —(CH₂)₂— —NH—C(═O)— K218 J013 T170 1502 —(CH₂)₂— —NH—C(═O)— K218 J014 T148 1503 —(CH₂)₂— —NH—C(═O)— K218 J044 T170 1504 —(CH₂)₂— —NH—C(═O)— K218 J045 T170 1505 —(CH₂)₂— —NH—C(═O)— K218 J045 T178 1506 —(CH₂)₂— —NH—C(═O)— K218 J045 T179 1507 —(CH₂)₂— —NH—C(═O)— K222 J007 T148 1508 —(CH₂)₂— —NH—C(═O)— K222 J010 T148 1509 —(CH₂)₂— —NH—C(═O)— K222 J013 T148 1510 —(CH₂)₂— —NH—C(═O)— K222 J014 T148 1511 —(CH₂)₂— —NH—C(═O)— K240 J045 T148 1512 —(CH₂)₂— —NH—C(═O)— K242 J045 T169 1513 —(CH₂)₂— —NH—C(═O)— K242 J045 T170 1514 —(CH₂)₂— —NH—C(═O)— K243 J045 T170 1515 —(CH₂)₂— —NH—C(═O)— K244 J045 T169 1516 —(CH₂)₂— —NH—C(═O)— K244 J045 T170 1517 —(CH₂)₂— —NH—C(═O)— K245 J045 T170 1518 —(CH₂)₂— —NH—C(═O)— K246 J045 T170 1519 —(CH₂)₂— —NH—C(═O)— K247 J012 T148 1520 —(CH₂)₂— —NH—C(═O)— K247 J045 T148 1521 —(CH₂)₂— —NH—C(═O)— K247 J045 T170 1522 —(CH₂)₂— —NH—C(═O)— K248 J045 T148 1523 —(CH₂)₂— —NH—C(═O)— K248 J045 T170 1524 —(CH₂)₂— —NH—C(═O)— K249 J007 T148 1525 —(CH₂)₂— —NH—C(═O)— K249 J008 T148 1526 —(CH₂)₂— —NH—C(═O)— K249 J010 T148 1527 —(CH₂)₂— —NH—C(═O)— K249 J013 T148 1528 —(CH₂)₂— —NH—C(═O)— K249 J014 T148 1529 —(CH₂)₂— —NH—C(═O)— K249 J045 T170 1530 —(CH₂)₂— —NH—C(═O)— K250 J045 T148 1531 —(CH₂)₂— —NH—C(═O)— K250 J045 T170 1532 —(CH₂)₂— —NH—C(═O)— K251 J045 T170 1533 —(CH₂)₂— —NH—C(═O)— K252 J045 T148 1534 —(CH₂)₂— —NH—C(═O)— K252 J045 T170 1535 —(CH₂)₂— —NH—C(═O)— K253 J045 T148 1536 —(CH₂)₂— —NH—C(═O)— K253 J045 T170 1537 —(CH₂)₂— —NH—C(═O)— K254 J007 T148 1538 —(CH₂)₂— —NH—C(═O)— K254 J008 T148 1539 —(CH₂)₂— —NH—C(═O)— K254 J010 T148 1540 —(CH₂)₂— —NH—C(═O)— K254 J012 T148 1541 —(CH₂)₂— —NH—C(═O)— K254 J013 T148 1542 —(CH₂)₂— —NH—C(═O)— K254 J014 T148 1543 —(CH₂)₂— —NH—C(═O)— K254 J044 T170 1544 —(CH₂)₂— —NH—C(═O)— K254 J045 T169 1545 —(CH₂)₂— —NH—C(═O)— K254 J045 T170 1546 —(CH₂)₂— —NH—C(═O)— K255 J012 T148 1547 —(CH₂)₂— —NH—C(═O)— K255 J045 T169 1548 —(CH₂)₂— —NH—C(═O)— K255 J045 T170 1549 —(CH₂)₂— —NH—C(═O)— K256 J012 T148 1550 —(CH₂)₂— —NH—C(═O)— K256 J039 T170 1551 —(CH₂)₂— —NH—C(═O)— K256 J044 T170 1552 —(CH₂)₂— —NH—C(═O)— K256 J045 T169 1553 —(CH₂)₂— —NH—C(═O)— K256 J045 T170 1554 —(CH₂)₂— —NH—C(═O)— K257 J012 T148 1555 —(CH₂)₂— —NH—C(═O)— K257 J039 T170 1556 —(CH₂)₂— —NH—C(═O)— K257 J044 T170 1557 —(CH₂)₂— —NH—C(═O)— K257 J045 T169 1558 —(CH₂)₂— —NH—C(═O)— K257 J045 T170 1559 —(CH₂)₂— —NH—C(═O)— K258 J012 T148 1560 —(CH₂)₂— —NH—C(═O)— K258 J045 T169 1561 —(CH₂)₂— —NH—C(═O)— K258 J045 T170 1562 —(CH₂)₂— —NH—C(═O)— K259 J012 T148 1563 —(CH₂)₂— —NH—C(═O)— K259 J039 T170 1564 —(CH₂)₂— —NH—C(═O)— K259 J044 T170 1565 —(CH₂)₂— —NH—C(═O)— K259 J045 T169 1566 —(CH₂)₂— —NH—C(═O)— K259 J045 T170 1567 —(CH₂)₂— —NH—C(═O)— K260 J012 T148 1568 —(CH₂)₂— —NH—C(═O)— K260 J045 T169 1569 —(CH₂)₂— —NH—C(═O)— K260 J045 T170 1570 —(CH₂)₂— —NH—C(═O)— K261 J012 T148 1571 —(CH₂)₂— —NH—C(═O)— K261 J045 T169 1572 —(CH₂)₂— —NH—C(═O)— K261 J045 T170 1573 —(CH₂)₂— —NH—C(═O)— K262 J007 T148 1574 —(CH₂)₂— —NH—C(═O)— K262 J008 T148 1575 —(CH₂)₂— —NH—C(═O)— K262 J010 T148 1576 —(CH₂)₂— —NH—C(═O)— K262 J012 T148 1577 —(CH₂)₂— —NH—C(═O)— K262 J013 T148 1578 —(CH₂)₂— —NH—C(═O)— K262 J014 T148 1579 —(CH₂)₂— —NH—C(═O)— K262 J044 T148 1580 —(CH₂)₂— —NH—C(═O)— K262 J044 T170 1581 —(CH₂)₂— —NH—C(═O)— K262 J044 T178 1582 —(CH₂)₂— —NH—C(═O)— K262 J045 T148 1583 —(CH₂)₂— —NH—C(═O)— K262 J045 T169 1584 —(CH₂)₂— —NH—C(═O)— K262 J045 T170 1585 —(CH₂)₂— —NH—C(═O)— K262 J045 T178 1586 —(CH₂)₂— —NH—C(═O)— K263 J007 T148 1587 —(CH₂)₂— —NH—C(═O)— K263 J008 T148 1588 —(CH₂)₂— —NH—C(═O)— K263 J010 T148 1589 —(CH₂)₂— —NH—C(═O)— K263 J012 T148 1590 —(CH₂)₂— —NH—C(═O)— K263 J012 T164 1591 —(CH₂)₂— —NH—C(═O)— K263 J013 T148 1592 —(CH₂)₂— —NH—C(═O)— K263 J013 T170 1593 —(CH₂)₂— —NH—C(═O)— K263 J014 T148 1594 —(CH₂)₂— —NH—C(═O)— K263 J039 T170 1595 —(CH₂)₂— —NH—C(═O)— K263 J044 T148 1596 —(CH₂)₂— —NH—C(═O)— K263 J044 T170 1597 —(CH₂)₂— —NH—C(═O)— K263 J044 T179 1598 —(CH₂)₂— —NH—C(═O)— K263 J045 T148 1599 —(CH₂)₂— —NH—C(═O)— K263 J045 T169 1600 —(CH₂)₂— —NH—C(═O)— K263 J045 T170 1601 —(CH₂)₂— —NH—C(═O)— K263 J045 T178 1602 —(CH₂)₂— —NH—C(═O)— K263 J045 T179 1603 —(CH₂)₂— —NH—C(═O)— K264 J012 T148 1604 —(CH₂)₂— —NH—C(═O)— K264 J045 T169 1605 —(CH₂)₂— —NH—C(═O)— K264 J045 T170 1606 —(CH₂)₂— —NH—C(═O)— K265 J012 T148 1607 —(CH₂)₂— —NH—C(═O)— K265 J044 T148 1608 —(CH₂)₂— —NH—C(═O)— K265 J044 T180 1609 —(CH₂)₂— —NH—C(═O)— K265 J045 T148 1610 —(CH₂)₂— —NH—C(═O)— K265 J045 T169 1611 —(CH₂)₂— —NH—C(═O)— K265 J045 T170 1612 —(CH₂)₂— —NH—C(═O)— K265 J045 T180 1613 —(CH₂)₂— —NH—C(═O)— K266 J012 T148 1614 —(CH₂)₂— —NH—C(═O)— K266 J045 T169 1615 —(CH₂)₂— —NH—C(═O)— K266 J045 T170 1616 —(CH₂)₂— —NH—C(═O)— K267 J012 T148 1617 —(CH₂)₂— —NH—C(═O)— K267 J045 T169 1618 —(CH₂)₂— —NH—C(═O)— K267 J045 T170 1619 —(CH₂)₂— —NH—C(═O)— K268 J012 T148 1620 —(CH₂)₂— —NH—C(═O)— K268 J045 T170 1621 —(CH₂)₂— —NH—C(═O)— K269 J012 T148 1622 —(CH₂)₂— —NH—C(═O)— K269 J045 T170 1623 —(CH₂)₂— —NH—C(═O)— K210 J012 T148 1624 —(CH₂)₂— —NH—C(═O)— K270 J045 T170 1625 —(CH₂)₂— —NH—C(═O)— K271 J012 T148 1626 —(CH₂)₂— —NH—C(═O)— K271 J045 T169 1627 —(CH₂)₂— —NH—C(═O)— K271 J045 T170 1628 —(CH₂)₂— —NH—C(═O)— K272 J012 T148 1629 —(CH₂)₂— —NH—C(═O)— K272 J045 T169 1630 —(CH₂)₂— —NH—C(═O)— K272 J045 T170 1631 —(CH₂)₂— —NH—C(═O)— K273 J012 T148 1632 —(CH₂)₂— —NH—C(═O)— K273 J045 T170 1633 —(CH₂)₂— —NH—C(═O)— K274 J012 T148 1634 —(CH₂)₂— —NH—C(═O)— K274 J045 T170 1635 —(CH₂)₂— —NH—C(═O)— K275 J007 T148 1636 —(CH₂)₂— —NH—C(═O)— K275 J008 T148 1637 —(CH₂)₂— —NH—C(═O)— K275 J010 T148 1638 —(CH₂)₂— —NH—C(═O)— K275 J012 T148 1639 —(CH₂)₂— —NH—C(═O)— K275 J013 T148 1640 —(CH₂)₂— —NH—C(═O)— K275 J014 T148 1641 —(CH₂)₂— —NH—C(═O)— K275 J044 T170 1642 —(CH₂)₂— —NH—C(═O)— K275 J045 T169 1643 —(CH₂)₂— —NH—C(═O)— K275 J045 T170 1644 —(CH₂)₂— —NH—C(═O)— K276 J007 T148 1645 —(CH₂)₂— —NH—C(═O)— K276 J008 T148 1646 —(CH₂)₂— —NH—C(═O)— K276 J010 T148 1647 —(CH₂)₂— —NH—C(═O)— K276 J012 T148 1648 —(CH₂)₂— —NH—C(═O)— K276 J012 T164 1649 —(CH₂)₂— —NH—C(═O)— K276 J013 T148 1650 —(CH₂)₂— —NH—C(═O)— K276 J013 T170 1651 —(CH₂)₂— —NH—C(═O)— K276 J014 T148 1652 —(CH₂)₂— —NH—C(═O)— K276 J044 T170 1653 —(CH₂)₂— —NH—C(═O)— K276 J045 T169 1654 —(CH₂)₂— —NH—C(═O)— K276 J045 T170 1655 —(CH₂)₂— —NH—C(═O)— K276 J045 T178 1656 —(CH₂)₂— —NH—C(═O)— K276 J045 T179 1657 —(CH₂)₂— —NH—C(═O)— K277 J045 T170 1658 —(CH₂)₂— —NH—C(═O)— K278 J045 T170 1659 —(CH₂)₂— —NH—C(═O)— K279 J045 T170 1660 —(CH₂)₂— —NH—C(═O)— K280 J012 T148 1661 —(CH₂)₂— —NH—C(═O)— K280 J045 T170 1662 —(CH₂)₂— —NH—C(═O)— K281 J045 T170 1663 —(CH₂)₂— —NH—C(═O)— K282 J045 T170 1664 —(CH₂)₂— —NH—C(═O)— K283 J045 T170 1665 —(CH₂)₂— —NH—C(═O)— K284 J045 T170 1666 —(CH₂)₂— —NH—C(═O)— K285 J045 T170 1667 —(CH₂)₂— —NH—C(═O)— K286 J045 T170 1668 —(CH₂)₂— —NH—C(═O)— K287 J045 T170 1669 —(CH₂)₂— —NH—C(═O)— K288 J045 T170 1670 —(CH₂)₂— —NH—C(═O)— K289 J007 T148 1671 —(CH₂)₂— —NH—C(═O)— K289 J008 T148 1672 —(CH₂)₂— —NH—C(═O)— K289 J010 T148 1673 —(CH₂)₂— —NH—C(═O)— K289 J012 T148 1674 —(CH₂)₂— —NH—C(═O)— K289 J013 T148 1675 —(CH₂)₂— —NH—C(═O)— K289 J014 T148 1676 —(CH₂)₂— —NH—C(═O)— K289 J044 T169 1677 —(CH₂)₂— —NH—C(═O)— K289 J044 T170 1678 —(CH₂)₂— —NH—C(═O)— K289 J045 T169 1679 —(CH₂)₂— —NH—C(═O)— K289 J045 T170 1680 —(CH₂)₂— —NH—C(═O)— K290 J045 T170 1681 —(CH₂)₂— —NH—C(═O)— K291 J045 T170 1682 —(CH₂)₂— —NH—C(═O)— K292 J045 T148 1683 —(CH₂)₂— —NH—C(═O)— K292 J045 T170 1684 —(CH₂)₂— —NH—C(═O)— K293 J007 T148 1685 —(CH₂)₂— —NH—C(═O)— K293 J008 T148 1686 —(CH₂)₂— —NH—C(═O)— K293 J010 T148 1687 —(CH₂)₂— —NH—C(═O)— K293 J012 T148 1688 —(CH₂)₂— —NH—C(═O)— K293 J013 T148 1689 —(CH₂)₂— —NH—C(═O)— K293 J014 T148 1690 —(CH₂)₂— —NH—C(═O)— K293 J044 T170 1691 —(CH₂)₂— —NH—C(═O)— K293 J045 T148 1692 —(CH₂)₂— —NH—C(═O)— K293 J045 T169 1693 —(CH₂)₂— —NH—C(═O)— K293 J045 T170 1694 —(CH₂)₂— —NH—C(═O)— K294 J045 T170 1695 —(CH₂)₂— —NH—C(═O)— K295 J045 T170 1696 —(CH₂)₂— —NH—C(═O)— K295/K296 J045 T148 1697 —(CH₂)₂— —NH—C(═O)— K296 J045 T170 1698 —(CH₂)₂— —NH—C(═O)— K297 J045 T170 1699 —(CH₂)₂— —NH—C(═O)— K298 J045 T148 1700 —(CH₂)₂— —NH—C(═O)— K298 J045 T170 1701 —(CH₂)₂— —NH—C(═O)— K299 J045 T170 1702 —(CH₂)₂— —NH—C(═O)— K300 J045 T170 1703 —(CH₂)₂— —NH—C(═O)— K301 J044 T170 1704 —(CH₂)₂— —NH—C(═O)— K301 J045 T169 1705 —(CH₂)₂— —NH—C(═O)— K301 J045 T170 1706 —(CH₂)₂— —NH—C(═O)— K302 J012 T148 1707 —(CH₂)₂— —NH—C(═O)— K302 J044 T170 1708 —(CH₂)₂— —NH—C(═O)— K302 J045 T170 1709 —(CH₂)₂— —NH—C(═O)— K303 J007 T148 1710 —(CH₂)₂— —NH—C(═O)— K303 J008 T148 1711 —(CH₂)₂— —NH—C(═O)— K303 J010 T148 1712 —(CH₂)₂— —NH—C(═O)— K303 J013 T148 1713 —(CH₂)₂— —NH—C(═O)— K303 J014 T148 1714 —(CH₂)₂— —NH—C(═O)— K303 J044 T170 1715 —(CH₂)₂— —NH—C(═O)— K303 J045 T148 1716 —(CH₂)₂— —NH—C(═O)— K303 J045 T169 1717 —(CH₂)₂— —NH—C(═O)— K303 J045 T170 1718 —(CH₂)₂— —NH—C(═O)— K304 J012 T148 1719 —(CH₂)₂— —NH—C(═O)— K304 J045 T148 1720 —(CH₂)₂— —NH—C(═O)— K304 J045 T170 1721 —(CH₂)₂— —NH—C(═O)— K305 J045 T148 1722 —(CH₂)₂— —NH—C(═O)— K305 J045 T170 1723 —(CH₂)₂— —NH—C(═O)— K306 J044 T170 1724 —(CH₂)₂— —NH—C(═O)— K306 J045 T170 1725 —(CH₂)₂— —NH—C(═O)— K307 J045 T170 1726 —(CH₂)₂— —NH—C(═O)— K308 J007 T148 1727 —(CH₂)₂— —NH—C(═O)— K308 J008 T148 1728 —(CH₂)₂— —NH—C(═O)— K308 J010 T148 1729 —(CH₂)₂— —NH—C(═O)— K308 J012 T148 1730 —(CH₂)₂— —NH—C(═O)— K308 J013 T148 1731 —(CH₂)₂— —NH—C(═O)— K308 J014 T148 1732 —(CH₂)₂— —NH—C(═O)— K308 J045 T170 1733 —(CH₂)₂— —NH—C(═O)— K309 J045 T170 1734 —(CH₂)₂— —NH—C(═O)— K310 J045 T170 1735 —(CH₂)₂— —NH—C(═O)— K311 J045 T170 1736 —(CH₂)₂— —NH—C(═O)— K312 J012 T148 1737 —(CH₂)₂— —NH—C(═O)— K312 J045 T170 1738 —(CH₂)₂— —NH—C(═O)— K313 J012 T148 1739 —(CH₂)₂— —NH—C(═O)— K313 J045 T148 1740 —(CH₂)₂— —NH—C(═O)— K313 J045 T170 1741 —(CH₂)₂— —NH—C(═O)— K314 J007 T148 1742 —(CH₂)₂— —NH—C(═O)— K314 J008 T148 1743 —(CH₂)₂— —NH—C(═O)— K314 J010 T148 1744 —(CH₂)₂— —NH—C(═O)— K314 J012 T148 1745 —(CH₂)₂— —NH—C(═O)— K314 J013 T148 1746 —(CH₂)₂— —NH—C(═O)— K314 J014 T148 1747 —(CH₂)₂— —NH—C(═O)— K314 J044 T170 1748 —(CH₂)₂— —NH—C(═O)— K314 J045 T148 1749 —(CH₂)₂— —NH—C(═O)— K314 J045 T169 1750 —(CH₂)₂— —NH—C(═O)— K314 J045 T170 1751 —(CH₂)₂— —NH—C(═O)— K315 J045 T148 1752 —(CH₂)₂— —NH—C(═O)— K315 J045 T170 1753 —(CH₂)₂— —NH—C(═O)— K316 J045 T148 1754 —(CH₂)₂— —NH—C(═O)— K316 J045 T170 1755 —(CH₂)₂— —NH—C(═O)— K317 J012 T148 1756 —(CH₂)₂— —NH—C(═O)— K317 J045 T170 1757 —(CH₂)₂— —NH—C(═O)— K318 J045 T170 1758 —(CH₂)₂— —NH—C(═O)— K319 J045 T148 1759 —(CH₂)₂— —NH—C(═O)— K319 J045 T170 1760 —(CH₂)₂— —NH—C(═O)— K320 J045 T170 1761 —(CH₂)₂— —NH—C(═O)— K321 J045 T170 1762 —(CH₂)₂— —NH—C(═O)— K322 J045 T170 1763 —(CH₂)₂— —NH—C(═O)— K323 J007 T148 1764 —(CH₂)₂— —NH—C(═O)— K323 J008 T148 1765 —(CH₂)₂— —NH—C(═O)— K323 J010 T148 1766 —(CH₂)₂— —NH—C(═O)— K323 J013 T148 1767 —(CH₂)₂— —NH—C(═O)— K323 J014 T148 1768 —(CH₂)₂— —NH—C(═O)— K323 J045 T169 1769 —(CH₂)₂— —NH—C(═O)— K323 J045 T170 1770 —(CH₂)₂— —NH—C(═O)— K326 J045 T170 1771 —(CH₂)₂— —NH—C(═O)— K332 J012 T148 1772 —(CH₂)₂— —NH—C(═O)— K332 J012 T164 1773 —(CH₂)₂— —NH—C(═O)— K332 J013 T148 1774 —(CH₂)₂— —NH—C(═O)— K332 J013 T170 1775 —(CH₂)₂— —NH—C(═O)— K332 J045 T170 1776 —(CH₂)₂— —NH—C(═O)— K332 J045 T178 1777 —(CH₂)₂— —NH—C(═O)— K332 J045 T179 1778 —(CH₂)₂— —NH—C(═O)— K333 J012 T148 1779 —(CH₂)₂— —NH—C(═O)— K333 J012 T164 1780 —(CH₂)₂— —NH—C(═O)— K333 J013 T148 1781 —(CH₂)₂— —NH—C(═O)— K333 J013 T170 1782 —(CH₂)₂— —NH—C(═O)— K333 J045 T170 1783 —(CH₂)₂— —NH—C(═O)— K333 J045 T178 1784 —(CH₂)₂— —NH—C(═O)— K333 J045 T179 1785 —(CH₂)₂— —NH—C(═O)— K335 J012 T148 1786 —(CH₂)₂— —NH—C(═O)— K335 J012 T164 1787 —(CH₂)₂— —NH—C(═O)— K335 J013 T148 1788 —(CH₂)₂— —NH—C(═O)— K335 J013 T170 1789 —(CH₂)₂— —NH—C(═O)— K335 J045 T170 1790 —(CH₂)₂— —NH—C(═O)— K335 J045 T178 1791 —(CH₂)₂— —NH—C(═O)— K335 J045 T179 1792 —(CH₂)₂— —NH—C(═O)— K336 J012 T148 1793 —(CH₂)₂— —NH—C(═O)— K336 J012 T164 1794 —(CH₂)₂— —NH—C(═O)— K336 J013 T148 1795 —(CH₂)₂— —NH—C(═O)— K336 J013 T170 1796 —(CH₂)₂— —NH—C(═O)— K336 J045 T170 1797 —(CH₂)₂— —NH—C(═O)— K336 J045 T178 1798 —(CH₂)₂— —NH—C(═O)— K336 J045 T179 1799 —(CH₂)₂— —NH—C(═O)— K340 J045 T170 1800 —(CH₂)₂— —NH—C(═O)— K343 J045 T170 1801 —(CH₂)₂— —NH—C(═O)— K345 J045 T169 1802 —(CH₂)₂— —NH—C(═O)— K346 J045 T169 1803 —(CH₂)₂— —NH—C(═O)— K346 J045 T170 1804 —(CH₂)₂— —NH—C(═O)— K355 J045 T148 1805 —(CH₂)₂— —NH—C(═O)— K356 J045 T148 1806 —(CH₂)₂— —NH—C(═O)— K357 J045 T148 1807 —(CH₂)₂— —NH—C(═O)— K357 J045 T170 1808 —(CH₂)₂— —NH—C(═O)— K358 J045 T148 1809 —(CH₂)₂— —NH—C(═O)— K358 J045 T170 1810 —(CH₂)₂— —NH—C(═O)— K359 J012 T170 1811 —(CH₂)₂— —NH—C(═O)— K359 J045 T170 1812 —(CH₂)₂— —NH—C(═O)— K360 J012 T170 1813 —(CH₂)₂— —NH—C(═O)— K360 J045 T170 1814 —(CH₂)₂— —NH—C(═O)— K361 J012 T170 1815 —(CH₂)₂— —NH—C(═O)— K361 J045 T170 1816 —(CH₂)₂— —NH—C(═O)— K362 J012 T170 1817 —(CH₂)₂— —NH—C(═O)— K362 J045 T170 1818 —(CH₂)₂— —NH—C(═O)— K363 J012 T170 1819 —(CH₂)₂— —NH—C(═O)— K363 J045 T170 1820 —(CH₂)₂— —NH—C(═O)— K364 J012 T170 1821 —(CH₂)₂— —NH—C(═O)— K364 J045 T170 1822 —(CH₂)₂— —NH—C(═O)— K365 J012 T170 1823 —(CH₂)₂— —NH—C(═O)— K365 J045 T148 1824 —(CH₂)₂— —NH—C(═O)— K365 J045 T170 1825 —(CH₂)₂— —NH—C(═O)— K366 J012 T170 1826 —(CH₂)₂— —NH—C(═O)— K366 J045 T170 1827 —(CH₂)₂— —NH—C(═O)— K367 J012 T170 1828 —(CH₂)₂— —NH—C(═O)— K367 J045 T148 1829 —(CH₂)₂— —NH—C(═O)— K367 J045 T170 1830 —(CH₂)₂— —NH—C(═O)— K368 J012 T170 1831 —(CH₂)₂— —NH—C(═O)— K368 J045 T170 1832 —(CH₂)₂— —NH—C(═O)— K369 J012 T170 1833 —(CH₂)₂— —NH—C(═O)— K369 J045 T148 1834 —(CH₂)₂— —NH—C(═O)— K369 J045 T170 1835 —(CH₂)₂— —NH—C(═O)— K370 J012 T170 1836 —(CH₂)₂— —NH—C(═O)— K370 J045 T170 1837 —(CH₂)₂— —NH—C(═O)— K371 J012 T170 1838 —(CH₂)₂— —NH—C(═O)— K371 J045 T170 1839 —(CH₂)₂— —NH—C(═O)— K372 J012 T170 1840 —(CH₂)₂— —NH—C(═O)— K372 J045 T170 1841 —(CH₂)₂— —NH—C(═O)— K373 J012 T170 1842 —(CH₂)₂— —NH—C(═O)— K373 J045 T170 1843 —(CH₂)₂— —NH—C(═O)— K374 J012 T148 1844 —(CH₂)₂— —NH—C(═O)— K374 J012 T170 1845 —(CH₂)₂— —NH—C(═O)— K374 J045 T170 1846 —(CH₂)₂— —NH—C(═O)— K375 J012 T148 1847 —(CH₂)₂— —NH—C(═O)— K375 J012 T170 1848 —(CH₂)₂— —NH—C(═O)— K375 J045 T170 1849 —(CH₂)₂— —NH—C(═O)— K376 J012 T148 1850 —(CH₂)₂— —NH—C(═O)— K376 J012 T170 1851 —(CH₂)₂— —NH—C(═O)— K376 J045 T170 1852 —(CH₂)₂— —NH—C(═O)— K377 J012 T148 1853 —(CH₂)₂— —NH—C(═O)— K377 J012 T170 1854 —(CH₂)₂— —NH—C(═O)— K377 J045 T170 1855 —(CH₂)₂— —NH—C(═O)— K378 J012 T148 1856 —(CH₂)₂— —NH—C(═O)— K378 J012 T170 1857 —(CH₂)₂— —NH—C(═O)— K378 J039 T170 1858 —(CH₂)₂— —NH—C(═O)— K378 J044 T170 1859 —(CH₂)₂— —NH—C(═O)— K378 J045 T169 1860 —(CH₂)₂— —NH—C(═O)— K378 J045 T170 1861 —(CH₂)₂— —NH—C(═O)— K379 J012 T148 1862 —(CH₂)₂— —NH—C(═O)— K379 J012 T170 1863 —(CH₂)₂— —NH—C(═O)— K379 J045 T169 1864 —(CH₂)₂— —NH—C(═O)— K379 J045 T170 1865 —(CH₂)₂— —NH—C(═O)— K380 J012 T148 1866 —(CH₂)₂— —NH—C(═O)— K380 J012 T170 1867 —(CH₂)₂— —NH—C(═O)— K380 J045 T170 1868 —(CH₂)₂— —NH—C(═O)— K381 J012 T148 1869 —(CH₂)₂— —NH—C(═O)— K381 J012 T170 1870 —(CH₂)₂— —NH—C(═O)— K381 J045 T169 1871 —(CH₂)₂— —NH—C(═O)— K381 J045 T170 1872 —(CH₂)₂— —NH—C(═O)— K382 J007 T148 1873 —(CH₂)₂— —NH—C(═O)— K382 J008 T148 1874 —(CH₂)₂— —NH—C(═O)— K382 J010 T148 1875 —(CH₂)₂— —NH—C(═O)— K382 J012 T148 1876 —(CH₂)₂— —NH—C(═O)— K382 J012 T170 1877 —(CH₂)₂— —NH—C(═O)— K382 J013 T148 1878 —(CH₂)₂— —NH—C(═O)— K382 J014 T148 1879 —(CH₂)₂— —NH—C(═O)— K382 J039 T170 1880 —(CH₂)₂— —NH—C(═O)— K382 J044 T170 1881 —(CH₂)₂— —NH—C(═O)— K382 J045 T169 1882 —(CH₂)₂— —NH—C(═O)— K382 J045 T170 1883 —(CH₂)₂— —NH—C(═O)— K383 J012 T170 1884 —(CH₂)₂— —NH—C(═O)— K383 J045 T170 1885 —(CH₂)₂— —NH—C(═O)— K384 J012 T148 1886 —(CH₂)₂— —NH—C(═O)— K384 J012 T170 1887 —(CH₂)₂— —NH—C(═O)— K384 J039 T170 1888 —(CH₂)₂— —NH—C(═O)— K384 J044 T170 1889 —(CH₂)₂— —NH—C(═O)— K384 J045 T169 1890 —(CH₂)₂— —NH—C(═O)— K384 J045 T170 1891 —(CH₂)₂— —NH—C(═O)— K385 J012 T148 1892 —(CH₂)₂— —NH—C(═O)— K385 J012 T170 1893 —(CH₂)₂— —NH—C(═O)— K385 J045 T169 1894 —(CH₂)₂— —NH—C(═O)— K385 J045 T170 1895 —(CH₂)₂— —NH—C(═O)— K386 J012 T148 1896 —(CH₂)₂— —NH—C(═O)— K386 J039 T170 1897 —(CH₂)₂— —NH—C(═O)— K386 J044 T170 1898 —(CH₂)₂— —NH—C(═O)— K386 J045 T170 1899 —(CH₂)₂— —NH—C(═O)— K387 J012 T148 1900 —(CH₂)₂— —NH—C(═O)— K387 J045 T170 1901 —(CH₂)₂— —NH—C(═O)— K388 J012 T148 1902 —(CH₂)₂— —NH—C(═O)— K388 J039 T170 1903 —(CH₂)₂— —NH—C(═O)— K388 J044 T170 1904 —(CH₂)₂— —NH—C(═O)— K388 J045 T170 1905 —(CH₂)₂— —NH—C(═O)— K389 J012 T148 1906 —(CH₂)₂— —NH—C(═O)— K389 J045 T170 1907 —(CH₂)₂— —NH—C(═O)— K390 J012 T148 1908 —(CH₂)₂— —NH—C(═O)— K390 J045 T170 1909 —(CH₂)₂— —NH—C(═O)— K391 J012 T148 1910 —(CH₂)₂— —NH—C(═O)— K391 J045 T170 1911 —(CH₂)₂— —NH—C(═O)— K392 J012 T148 1912 —(CH₂)₂— —NH—C(═O)— K392 J045 T170 1913 —(CH₂)₂— —NH—C(═O)— K393 J012 T148 1914 —(CH₂)₂— —NH—C(═O)— K393 J045 T170 1915 —(CH₂)₂— —NH—C(═O)— K394 J012 T148 1916 —(CH₂)₂— —NH—C(═O)— K394 J045 T170 1917 —(CH₂)₂— —NH—C(═O)— K398 J012 T148 1918 —(CH₂)₂— —NH—C(═O)— K399 J010 T148 1919 —(CH₂)₂— —NH—C(═O)— K399 J010 T170 1920 —(CH₂)₂— —NH—C(═O)— K399 J012 T148 1921 —(CH₂)₂— —NH—C(═O)— K399 J013 T148 1922 —(CH₂)₂— —NH—C(═O)— K399 J013 T170 1923 —(CH₂)₂— —NH—C(═O)— K399 J044 T170 1924 —(CH₂)₂— —NH—C(═O)— K399 J045 T170 1925 —(CH₂)₂— —NH—C(═O)— K399 J146 T148 1926 —(CH₂)₂— —NH—C(═O)— K399 J147 T148 1927 —(CH₂)₂— —NH—C(═O)— K399 J150 T148 1928 —(CH₂)₂— —NH—C(═O)— K399 J150 T170 1929 —(CH₂)₂— —NH—C(═O)— K399 J151 T148 1930 —(CH₂)₂— —NH—C(═O)— K399 J159 T148 1931 —(CH₂)₂— —NH—C(═O)— K399 J159 T170 1932 —(CH₂)₂— —NH—C(═O)— K400 J012 T148 1933 —(CH₂)₂— —NH—C(═O)— K400 J013 T170 1934 —(CH₂)₂— —NH—C(═O)— K400 J045 T170 1935 —(CH₂)₂— —NH—C(═O)— K400 J151 T148 1936 —(CH₂)₂— —NH—C(═O)— K400 J151 T170 1937 —(CH₂)₂— —NH—C(═O)— K401 J012 T148 1938 —(CH₂)₂— —NH—C(═O)— K401 J045 T170 1939 —(CH₂)₂— —NH—C(═O)— K402 J012 T148 1940 —(CH₂)₂— —NH—C(═O)— K402 J045 T170 1941 —(CH₂)₂— —NH—C(═O)— K402 J151 T170 1942 —(CH₂)₂— —NH—C(═O)— K402 J159 T148 1943 —(CH₂)₂— —NH—C(═O)— K402 J159 T170 1944 —(CH₂)₂— —NH—C(═O)— K403 J012 T148 1945 —(CH₂)₂— —NH—C(═O)— K403 J013 T148 1946 —(CH₂)₂— —NH—C(═O)— K403 J013 T170 1947 —(CH₂)₂— —NH—C(═O)— K403 J044 T170 1948 —(CH₂)₂— —NH—C(═O)— K403 J045 T170 1949 —(CH₂)₂— —NH—C(═O)— K403 J151 T148 1950 —(CH₂)₂— —NH—C(═O)— K403 J151 T170 1951 —(CH₂)₂— —NH—C(═O)— K403 J158 T170 1952 —(CH₂)₂— —NH—C(═O)— K404 J012 T148 1953 —(CH₂)₂— —NH—C(═O)— K405 J012 T148 1954 —(CH₂)₂— —NH—C(═O)— K406 J012 T148 1955 —(CH₂)₂— —NH—C(═O)— K406 J045 T170 1956 —(CH₂)₂— —NH—C(═O)— K407 J012 T148 1957 —(CH₂)₂— —NH—C(═O)— K407 J013 T148 1958 —(CH₂)₂— —NH—C(═O)— K407 J013 T170 1959 —(CH₂)₂— —NH—C(═O)— K407 J044 T170 1960 —(CH₂)₂— —NH—C(═O)— K407 J045 T170 1961 —(CH₂)₂— —NH—C(═O)— K408 J012 T148 1962 —(CH₂)₂— —NH—C(═O)— K409 J012 T148 1963 —(CH₂)₂— —NH—C(═O)— K409 J045 T170 1964 —(CH₂)₂— —NH—C(═O)— K410 J012 T148 1965 —(CH₂)₂— —NH—C(═O)— K411 J012 T148 1966 —(CH₂)₂— —NH—C(═O)— K411 J045 T170 1967 —(CH₂)₂— —NH—C(═O)— K412 J012 T148 1968 —(CH₂)₂— —NH—C(═O)— K413 J012 T148 1969 —(CH₂)₂— —NH—C(═O)— K414 J012 T148 1970 —(CH₂)₂— —NH—C(═O)— K414 J044 T170 1971 —(CH₂)₂— —NH—C(═O)— K414 J045 T170 1972 —(CH₂)₂— —NH—C(═O)— K415 J012 T148 1973 —(CH₂)₂— —NH—C(═O)— K415 J013 T148 1974 —(CH₂)₂— —NH—C(═O)— K415 J013 T170 1975 —(CH₂)₂— —NH—C(═O)— K415 J044 T170 1976 —(CH₂)₂— —NH—C(═O)— K415 J045 T170 1977 —(CH₂)₂— —NH—C(═O)— K415 J151 T148 1978 —(CH₂)₂— —NH—C(═O)— K415 J151 T170 1979 —(CH₂)₂— —NH—C(═O)— K415 J158 T170 1980 —(CH₂)₂— —NH—C(═O)— K416 J012 T148 1981 —(CH₂)₂— —NH—C(═O)— K417 J012 T148 1982 —(CH₂)₂— —NH—C(═O)— K418 J012 T148 1983 —(CH₂)₂— —NH—C(═O)— K419 J012 T148 1984 —(CH₂)₂— —NH—C(═O)— K419 J045 T170 1985 —(CH₂)₂— —NH—C(═O)— K420 J012 T148 1986 —(CH₂)₂— —NH—C(═O)— K420 J013 T148 1987 —(CH₂)₂— —NH—C(═O)— K420 J013 T170 1988 —(CH₂)₂— —NH—C(═O)— K420 J044 T170 1989 —(CH₂)₂— —NH—C(═O)— K420 J045 T148 1990 —(CH₂)₂— —NH—C(═O)— K420 J045 T170 1991 —(CH₂)₂— —NH—C(═O)— K420 J149 T148 1992 —(CH₂)₂— —NH—C(═O)— K420 J150 T148 1993 —(CH₂)₂— —NH—C(═O)— K420 J150 T170 1994 —(CH₂)₂— —NH—C(═O)— K420 J151 T148 1995 —(CH₂)₂— —NH—C(═O)— K420 J151 T170 1996 —(CH₂)₂— —NH—C(═O)— K420 J158 T170 1997 —(CH₂)₂— —NH—C(═O)— K421 J012 T148 1998 —(CH₂)₂— —NH—C(═O)— K422 J012 T148 1999 —(CH₂)₂— —NH—C(═O)— K423 J012 T148 2000 —(CH₂)₂— —NH—C(═O)— K424 J012 T148 2001 —(CH₂)₂— —NH—C(═O)— K425 J012 T148 2002 —(CH₂)₂— —NH—C(═O)— K426 J012 T148 2003 —(CH₂)₂— —NH—C(═O)— K200 J022 T170 2004 —(CH₂)₂— —NH—C(═O)— K357 J012 T148 2005 —(CH₂)₂— —NH—C(═O)—NH— K005 J045 T148 2006 —(CH₂)₂— —NH—C(═O)—NH— K008 J045 T148 2007 —(CH₂)₂— —NH—C(═O)—NH— K023 J012 T148 2008 —(CH₂)₂— —NH—C(═O)—NH— K033 J012 T148 2009 —(CH₂)₂— —NH—C(═O)—NH— K077 J045 T148 2010 —(CH₂)₂— —NH—C(═O)—NH— K102 J045 T148 2011 —(CH₂)₂— —NH—C(═O)—NH— K102 J045 T170 2012 —(CH₂)₂— —NH—C(═O)—NH— K106 J045 T148 2013 —(CH₂)₂— —NH—C(═O)—NH— K336 J012 T148 2014 —(CH₂)₂— —NH—C(═O)—NH— K204 J045 T148 2015 —(CH₂)₂— —NH—C(═O)—NH— K204 J045 T170 2016 —(CH₂)₂— —NH—C(═O)—NH— K223 J045 T148 2017 —(CH₂)₂— —NH—C(═O)—NH— K230 J012 T148 2018 —(CH₂)₂— —NH—C(═O)—NH— K231 J012 T148 2019 —(CH₂)₂— —NH—C(═O)—NH— K248 J045 T148 2020 —(CH₂)₂— —NH—C(═O)—NH— K249 J045 T148 2021 —(CH₂)₂— —NH—C(═O)—NH— K250 J045 T148 2022 —(CH₂)₂— —NH—C(═O)—NH— K278 J012 T148 2023 —(CH₂)₂— —NH—C(═O)—NH— K277 J045 T148 2024 —(CH₂)₂— —NH—C(═O)—NH— K277 J045 T170 2025 —(CH₂)₂— —NH—C(═O)—NH— K278 J045 T148 2026 —(CH₂)₂— —NH—C(═O)—NH— K278 J045 T170 2027 —(CH₂)₂— —NH—C(═O)—NH— K279 J045 T148 2028 —(CH₂)₂— —NH—C(═O)—NH— K286 J045 T148 2029 —(CH₂)₂— —NH—C(═O)—NH— K324 J045 T148 2030 —(CH₂)₂— —NH—C(═O)—NH— K324 J045 T170 2031 —(CH₂)₂— —NH—C(═O)—NH— K325 J012 T148 2032 —(CH₂)₂— —NH—C(═O)—NH— K325 J045 T148 2033 —(CH₂)₂— —NH—C(═O)—NH— K325 J045 T170 2034 —(CH₂)₂— —NH—C(═O)—NH— K326 J045 T148 2035 —(CH₂)₂— —NH—C(═O)—NH— K326 J045 T169 2036 —(CH₂)₂— —NH—C(═O)—NH— K326 J045 T170 2037 —(CH₂)₂— —NH—C(═O)—NH— K327 J045 T170 2038 —(CH₂)₂— —NH—C(═O)—NH— K328 J045 T170 2039 —(CH₂)₂— —NH—C(═O)—NH— K329 J045 T170 2040 —(CH₂)₂— —NH—C(═O)—NH— K330 J012 T148 2041 —(CH₂)₂— —NH—C(═O)—NH— K330 J045 T170 2042 —(CH₂)₂— —NH—C(═O)—NH— K331 J012 T148 2043 —(CH₂)₂— —NH—C(═O)—NH— K331 J045 T170 2044 —(CH₂)₂— —NH—C(═O)—NH— K332 J045 T169 2045 —(CH₂)₂— —NH—C(═O)—NH— K332 J045 T170 2046 —(CH₂)₂— —NH—C(═O)—NH— K333 J012 T148 2047 —(CH₂)₂— —NH—C(═O)—NH— K333 J044 T170 2048 —(CH₂)₂— —NH—C(═O)—NH— K333 J045 T169 2049 —(CH₂)₂— —NH—C(═O)—NH— K333 J045 T170 2050 —(CH₂)₂— —NH—C(═O)—NH— K334 J045 T170 2051 —(CH₂)₂— —NH—C(═O)—NH— K335 J044 T170 2052 —(CH₂)₂— —NH—C(═O)—NH— K335 J045 T148 2053 —(CH₂)₂— —NH—C(═O)—NH— K335 J045 T170 2054 —(CH₂)₂— —NH—C(═O)—NH— K336 J012 T170 2055 —(CH₂)₂— —NH—C(═O)—NH— K336 J044 T170 2056 —(CH₂)₂— —NH—C(═O)—NH— K336 J045 T148 2057 —(CH₂)₂— —NH—C(═O)—NH— K336 J045 T169 2058 —(CH₂)₂— —NH—C(═O)—NH— K336 J045 T170 2059 —(CH₂)₂— —NH—C(═O)—NH— K337 J045 T170 2060 —(CH₂)₂— —NH—C(═O)—NH— K338 J045 T148 2061 —(CH₂)₂— —NH—C(═O)—NH— K338 J045 T170 2062 —(CH₂)₂— —NH—C(═O)—NH— K339 J045 T148 2063 —(CH₂)₂— —NH—C(═O)—NH— K339 J045 T170 2064 —(CH₂)₂— —NH—C(═O)—NH— K340 J012 T148 2065 —(CH₂)₂— —NH—C(═O)—NH— K340 J045 T148 2066 —(CH₂)₂— —NH—C(═O)—NH— K340 J045 T169 2067 —(CH₂)₂— —NH—C(═O)—NH— K340 J045 T170 2068 —(CH₂)₂— —NH—C(═O)—NH— K341 J045 T148 2069 —(CH₂)₂— —NH—C(═O)—NH— K341 J045 T170 2070 —(CH₂)₂— —NH—C(═O)—NH— K342 J045 T148 2071 —(CH₂)₂— —NH—C(═O)—NH— K342 J045 T170 2072 —(CH₂)₂— —NH—C(═O)—NH— K343 J045 T148 2073 —(CH₂)₂— —NH—C(═O)—NH— K343 J045 T170 2074 —(CH₂)₂— —NH—C(═O)—NH— K344 J045 T170 2075 —(CH₂)₂— —NH—C(═O)—NH— K345 J045 T170 2076 —(CH₂)₂— —NH—C(═O)—NH— K346 J045 T170 2077 —(CH₂)₂— —NH—C(═O)—NH— K347 J045 T170 2078 —(CH₂)₂— —NH—C(═O)—NH— K348 J045 T148 2079 —(CH₂)₂— —NH—C(═O)—NH— K348 J045 T170 2080 —(CH₂)₂— —NH—C(═O)—NH— K349 J045 T170 2081 —(CH₂)₂— —NH—C(═O)—NH— K350 J045 T148 2082 —(CH₂)₂— —NH—C(═O)—NH— K350 J045 T170 2083 —(CH₂)₂— —NH—C(═O)—NH— K351 J045 T148 2084 —(CH₂)₂— —NH—C(═O)—NH— K351 J045 T170 2085 —(CH₂)₂— —NH—C(═O)—NH— K352 J045 T148 2086 —(CH₂)₂— —NH—C(═O)—NH— K352 J045 T170 2087 —(CH₂)₂— —NH—C(═O)—NH— K353 J045 T148 2088 —(CH₂)₂— —NH—C(═O)—NH— K353 J045 T170 2089 —(CH₂)₂— —NH—C(═O)—NH— K354 J045 T148 2090 —(CH₂)₂— —NH—C(═O)—NH— K354 J045 T170 2091 —(CH₂)₂— —NH—C(═O)—NH— K355 J045 T170 2092 —(CH₂)₂— —NH—C(═O)—NH— K356 J045 T170 2093 —(CH₂)₂— —NH—C(═O)—NH— K359 J045 T148 2094 —(CH₂)₂— —NH—C(═O)—NH— K360 J045 T148 2095 —(CH₂)₂— —NH—C(═O)—NH— K362 J045 T148 2096 —(CH₂)₂— —NH—C(═O)—NH— K361 J045 T148 2097 —(CH₂)₂— —NH—C(═O)—NH— K362 J045 T170 2098 —(CH₂)₂— —NH—C(═O)—NH— K364 J045 T170 2099 —(CH₂)₂— —NH—C(═O)—NH— K370 J045 T148 2100 —(CH₂)₂— —NH—C(═O)—NH— K371 J045 T148 2101 —(CH₂)₂— —NH—C(═O)—NH— K373 J045 T148 2102 —(CH₂)₂— —NH—C(═O)—NH— K431 J045 T170 2103 —(CH₂)₂— —NH—C(═O)—NH— K395 J012 T148 2104 —(CH₂)₂— —NH—C(═O)—NH— K395 J045 T170 2105 —(CH₂)₂— —NH—C(═O)—NH— K396 J012 T148 2106 —(CH₂)₂— —NH—C(═O)—NH— K396 J045 T170 2107 —(CH₂)₂— —NH—C(═O)—NH— K397 J012 T148 2108 —(CH₂)₂— —NH—C(═O)—NH— K397 J045 T170 2109 —(CH₂)₂— —NH—C(═O)— K241 J045 T148 2110 —(CH₂)₂— —NH—C(═O)—O— K005 J001 T148 2111 —(CH₂)₂— —NH—C(═O)—O— K005 J007 T148 2112 —(CH₂)₂— —NH—C(═O)—O— K005 J008 T148 2113 —(CH₂)₂— —NH—C(═O)—O— K005 J009 T170 2114 —(CH₂)₂— —NH—C(═O)—O— K005 J010 T148 2115 —(CH₂)₂— —NH—C(═O)—O— K005 J011 T170 2116 —(CH₂)₂— —NH—C(═O)—O— K005 J012 T170 2117 —(CH₂)₂— —NH—C(═O)—O— K005 J013 T148 2118 —(CH₂)₂— —NH—C(═O)—O— K005 J014 T148 2119 —(CH₂)₂— —NH—C(═O)—O— K005 J015 T170 2120 —(CH₂)₂— —NH—C(═O)—O— K005 J026 T001 2121 —(CH₂)₂— —NH—C(═O)—O— K005 J026 T148 2122 —(CH₂)₂— —NH—C(═O)—O— K005 J026 T170 2123 —(CH₂)₂— —NH—C(═O)—O— K005 J037 T170 2124 —(CH₂)₂— —NH—C(═O)—O— K005 J039 T170 2125 —(CH₂)₂— —NH—C(═O)—O— K005 J043 T170 2126 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T072 2127 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T074 2128 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T180 2129 —(CH₂)₂— —NH—C(═O)—O— K005 J047 T170 2130 —(CH₂)₂— —NH—C(═O)—O— K005 J079 T170 2131 —(CH₂)₂— —NH—C(═O)—O— K005 J080 T148 2132 —(CH₂)₂— —NH—C(═O)—O— K005 J081 T148 2133 —(CH₂)₂— —NH—C(═O)—O— K005 J082 T148 2134 —(CH₂)₂— —NH—C(═O)—O— K005 J090 T148 2135 —(CH₂)₂— —NH—C(═O)—O— K005 J092 T148 2136 —(CH₂)₂— —NH—C(═O)—O— K005 J103 T170 2137 —(CH₂)₂— —NH—C(═O)—O— K005 J104 T170 2138 —(CH₂)₂— —NH—C(═O)—O— K005 J105 T170 2139 —(CH₂)₂— —NH—C(═O)—O— K005 J106 T170 2140 —(CH₂)₂— —NH—C(═O)—O— K005 J107 T170 2141 —(CH₂)₂— —NH—C(═O)—O— K005 J140 T001 2142 —(CH₂)₂— —NH—C(═O)—O— K005 J140 T148 2143 —(CH₂)₂— —NH—C(═O)—O— K005 J140 T170 2144 —(CH₂)₂— —NH—C(═O)—O— K005 J144 T148 2145 —(CH₂)₂— —NH—C(═O)—O— K005 J146 T148 2146 —(CH₂)₂— —NH—C(═O)—O— K199 J045 T148 2147 —(CH₂)₂— —NH—C(═O)—O— K223 J045 T148 2148 —(CH₂)₂— —NH—C(═O)—O— K198 J045 T148 2149 —(CH₂)₂— —NH—S(═O)₂— K200 J012 T148 2150 —(CH₂)₂— —NH—S(═O)₂— K200 J044 T170 2151 —(CH₂)₂— —NH—S(═O)₂— K200 J045 T170 2152 —(CH₂)₂— —NH—S(═O)₂— K223 J012 T148 2153 —(CH₂)₂— —NH—S(═O)₂— K223 J044 T170 2154 —(CH₂)₂— —NH—S(═O)₂— K230 J044 T170 2155 —(CH₂)₂— —NH—S(═O)₂— K230 J045 T170 2156 —(CH₂)₂— —NH—S(═O)₂— K231 J044 T170 2157 —(CH₂)₂— —NH—S(═O)₂— K231 J045 T170 2158 —(CH₂)₃— —C(═O)— K108 J001 T148 2159 —(CH₂)₃— —C(═O)— K108 J022 T170 2160 —(CH₂)₃— —C(═O)— K109 J029 T170 2161 —(CH₂)₃— —C(═O)— K112 J012 T148 2162 —(CH₂)₃— —C(═O)— K112 J012 T170 2163 —(CH₂)₃— —C(═O)— K112 J037 T170 2164 —(CH₂)₃— —C(═O)— K112 J043 T170 2165 —(CH₂)₃— —C(═O)— K112 J138 T148 2166 —(CH₂)₃— —C(═O)— K112 J138 T170 2167 —(CH₂)₃— —C(═O)— K112 J144 T148 2168 —(CH₂)₃— —C(═O)— K112 J144 T164 2169 —(CH₂)₃— —C(═O)— K112 J144 T169 2170 —(CH₂)₃— —C(═O)— K112 J144 T170 2171 —(CH₂)₃— —C(═O)— K116 J012 T148 2172 —(CH₂)₃— —C(═O)— K121 J043 T170 2173 —(CH₂)₃— —C(═O)— K129 J012 T148 2174 —(CH₂)₃— —C(═O)— K136 J044 T170 2175 —(CH₂)₃— —C(═O)— K137 J012 T148 2176 —(CH₂)₃— —C(═O)— K137 J012 T170 2177 —(CH₂)₃— —C(═O)— K137 J045 T170 2178 —(CH₂)₃— —C(═O)— K138 J079 T170 2179 —(CH₂)₃— —C(═O)— K139 J012 T148 2180 —(CH₂)₃— —C(═O)— K142 J012 T148 2181 —(CH₂)₃— —C(═O)— K143 J012 T148 2182 —(CH₂)₃— —C(═O)— K144 J012 T148 2183 —(CH₂)₃— —C(═O)— K144 J043 T148 2184 —(CH₂)₃— —C(═O)— K144 J043 T170 2185 —(CH₂)₃— —C(═O)— K144 J138 T148 2186 —(CH₂)₃— —C(═O)— K144 J138 T170 2187 —(CH₂)₃— —C(═O)— K144 J144 T148 2188 —(CH₂)₃— —C(═O)— K144 J144 T170 2189 —(CH₂)₃— —C(═O)— K147 J012 T148 2190 —(CH₂)₃— —C(═O)— K147 J138 T170 2191 —(CH₂)₃— —C(═O)— K148 J012 T148 2192 —(CH₂)₃— —C(═O)— K148 J139 T170 2193 —(CH₂)₃— —C(═O)— K150 J012 T148 2194 —(CH₂)₃— —C(═O)— K154 J012 T148 2195 —(CH₂)₃— —C(═O)— K166 J012 T148 2196 —(CH₂)₃— —C(═O)— K166 J144 T170 2197 —(CH₂)₃— —C(═O)— K170 J007 T170 2198 —(CH₂)₃— —C(═O)— K172 J012 T170 2199 —(CH₂)₃— —C(═O)— K237 J012 T148 2200 —(CH₂)₃— —C(═O)— K391 J144 T170 2201 —(CH₂)₃— —C(═O)—NH— K004 J012 T148 2202 —(CH₂)₃— —C(═O)—NH— K009 J001 T148 2203 —(CH₂)₃— —C(═O)—NH— K009 J007 T148 2204 —(CH₂)₃— —C(═O)—NH— K009 J007 T164 2205 —(CH₂)₃— —C(═O)—NH— K009 J007 T169 2206 —(CH₂)₃— —C(═O)—NH— K009 J007 T170 2207 —(CH₂)₃— —C(═O)—NH— K009 J012 T148 2208 —(CH₂)₃— —C(═O)—NH— K009 J037 T170 2209 —(CH₂)₃— —C(═O)—NH— K012 J001 T148 2210 —(CH₂)₃— —C(═O)—NH— K013 J012 T148 2211 —(CH₂)₃— —C(═O)—NH— K013 J012 T170 2212 —(CH₂)₃— —C(═O)—NH— K023 J012 T148 2213 —(CH₂)₃— —C(═O)—NH— K023 J029 T148 2214 —(CH₂)₃— —C(═O)—NH— K023 J029 T164 2215 —(CH₂)₃— —C(═O)—NH— K023 J029 T169 2216 —(CH₂)₃— —C(═O)—NH— K023 J029 T170 2217 —(CH₂)₃— —C(═O)—NH— K023 J043 T170 2218 —(CH₂)₃— —C(═O)—NH— K029 J012 T148 2219 —(CH₂)₃— —C(═O)—NH— K029 J044 T148 2220 —(CH₂)₃— —C(═O)—NH— K029 J044 T164 2221 —(CH₂)₃— —C(═O)—NH— K029 J044 T169 2222 —(CH₂)₃— —C(═O)—NH— K029 J044 T170 2223 —(CH₂)₃— —C(═O)—NH— K029 J045 T170 2224 —(CH₂)₃— —C(═O)—NH— K033 J012 T148 2225 —(CH₂)₃— —C(═O)—NH— K033 J043 T148 2226 —(CH₂)₃— —C(═O)—NH— K033 J043 T164 2227 —(CH₂)₃— —C(═O)—NH— K033 J043 T169 2228 —(CH₂)₃— —C(═O)—NH— K033 J043 T170 2229 —(CH₂)₃— —C(═O)—NH— K033 J044 T170 2230 —(CH₂)₃— —C(═O)—NH— K034 J012 T148 2231 —(CH₂)₃— —C(═O)—NH— K034 J045 T148 2232 —(CH₂)₃— —C(═O)—NH— K034 J045 T164 2233 —(CH₂)₃— —C(═O)—NH— K034 J045 T169 2234 —(CH₂)₃— —C(═O)—NH— K034 J045 T170 2235 —(CH₂)₃— —C(═O)—NH— K034 J079 T170 2236 —(CH₂)₃— —C(═O)—NH— K077 J138 T170 2237 —(CH₂)₃— —C(═O)—NH— K078 J139 T170 2238 —(CH₂)₃— —C(═O)—NH— K101 J144 T170 2239 —(CH₂)₃— —C(═O)—NH— K102 J007 T170 2240 —(CH₂)₃— —C(═O)—NH— K102 J012 T148 2241 —(CH₂)₃— —C(═O)—NH— K102 J012 T170 2242 —(CH₂)₃— —C(═O)—NH— K102 J079 T148 2243 —(CH₂)₃— —C(═O)—NH— K102 J079 T164 2244 —(CH₂)₃— —C(═O)—NH— K102 J079 T169 2245 —(CH₂)₃— —C(═O)—NH— K102 J079 T170 2246 —(CH₂)₃— —C(═O)—NH— K103 J012 T148 2247 —(CH₂)₃— —C(═O)—NH— K103 J138 T148 2248 —(CH₂)₃— —C(═O)—NH— K103 J138 T164 2249 —(CH₂)₃— —C(═O)—NH— K103 J138 T169 2250 —(CH₂)₃— —C(═O)—NH— K103 J138 T170 2251 —(CH₂)₃— —C(═O)—NH— K104 J012 T148 2252 —(CH₂)₃— —C(═O)—NH— K104 J012 T170 2253 —(CH₂)₃— —C(═O)—NH— K104 J139 T148 2254 —(CH₂)₃— —C(═O)—NH— K104 J139 T164 2255 —(CH₂)₃— —C(═O)—NH— K104 J139 T169 2256 —(CH₂)₃— —C(═O)—NH— K104 J139 T170 2257 —(CH₂)₃— —C(═O)—NH— K108 J012 T148 2258 —(CH₂)₃— —C(═O)—NH— K198 J012 T148 2259 —(CH₂)₃— —C(═O)—NH— K198 J022 T170 2260 —(CH₂)₃— —C(═O)—NH— K200 J012 T148 2261 —(CH₂)₃— —C(═O)—NH— K200 J029 T170 2262 —(CH₂)₃— —C(═O)—NH— K201 J012 T148 2263 —(CH₂)₃— —C(═O)—NH— K201 J037 T170 2264 —(CH₂)₃— —C(═O)—NH— K204 J002 T148 2265 —(CH₂)₃— —C(═O)—NH— K204 J012 T148 2266 —(CH₂)₃— —C(═O)—NH— K204 J012 T170 2267 —(CH₂)₃— —C(═O)—NH— K204 J043 T148 2268 —(CH₂)₃— —C(═O)—NH— K204 J043 T170 2269 —(CH₂)₃— —C(═O)—NH— K204 J138 T170 2270 —(CH₂)₃— —C(═O)—NH— K204 J139 T148 2271 —(CH₂)₃— —C(═O)—NH— K204 J144 T148 2272 —(CH₂)₃— —C(═O)—NH— K204 J144 T170 2273 —(CH₂)₃— —C(═O)—NH— K215 J012 T148 2274 —(CH₂)₃— —C(═O)—NH— K216 J007 T170 2275 —(CH₂)₃— —C(═O)—NH— K216 J012 T148 2276 —(CH₂)₃— —C(═O)—NH— K216 J012 T164 2277 —(CH₂)₃— —C(═O)—NH— K216 J012 T170 2278 —(CH₂)₃— —C(═O)—NH— K216 J022 T170 2279 —(CH₂)₃— —C(═O)—NH— K216 J029 T170 2280 —(CH₂)₃— —C(═O)—NH— K216 J037 T170 2281 —(CH₂)₃— —C(═O)—NH— K216 J043 T148 2282 —(CH₂)₃— —C(═O)—NH— K216 J043 T170 2283 —(CH₂)₃— —C(═O)—NH— K216 J044 T169 2284 —(CH₂)₃— —C(═O)—NH— K216 J044 T170 2285 —(CH₂)₃— —C(═O)—NH— K216 J045 T170 2286 —(CH₂)₃— —C(═O)—NH— K216 J079 T170 2287 —(CH₂)₃— —C(═O)—NH— K216 J138 T148 2288 —(CH₂)₃— —C(═O)—NH— K216 J138 T170 2289 —(CH₂)₃— —C(═O)—NH— K216 J139 T170 2290 —(CH₂)₃— —C(═O)—NH— K216 J144 T148 2291 —(CH₂)₃— —C(═O)—NH— K216 J144 T170 2292 —(CH₂)₃— —C(═O)—NH— K223 J001 T148 2293 —(CH₂)₃— —C(═O)—NH— K223 J045 T170 2294 —(CH₂)₃— —C(═O)—NH— K224 J079 T170 2295 —(CH₂)₃— —C(═O)—NH— K225 J138 T170 2296 —(CH₂)₃— —C(═O)—NH— K229 J012 T148 2297 —(CH₂)₃— —C(═O)—NH— K229 J139 T170 2298 —(CH₂)₃— —C(═O)—NH— K234 J012 T148 2299 —(CH₂)₃— —C(═O)—NH— K198 J001 T148 2300 —(CH₂)₃— —C(═O)—NH— K244 J001 T148 2301 —(CH₂)₃— —C(═O)—NH— K246 J001 T148 2302 —(CH₂)₃— —C(═O)—NH— K280 J012 T148 2303 —(CH₂)₃— —C(═O)—NH— K293 J144 T170 2304 —(CH₂)₃— —C(═O)—NH— K323 J007 T170 2305 —(CH₂)₃— —C(═O)—NH— K324 J012 T148 2306 —(CH₂)₃— —C(═O)—NH— K324 J012 T170 2307 —(CH₂)₃— —C(═O)—NH— K325 J022 T170 2308 —(CH₂)₃— —C(═O)—NH— K326 J029 T170 2309 —(CH₂)₃— —C(═O)—NH— K327 J037 T170 2310 —(CH₂)₃— —C(═O)—NH— K333 J007 T170 2311 —(CH₂)₃— —C(═O)—NH— K333 J012 T148 2312 —(CH₂)₃— —C(═O)—NH— K333 J012 T170 2313 —(CH₂)₃— —C(═O)—NH— K333 J022 T170 2314 —(CH₂)₃— —C(═O)—NH— K333 J029 T170 2315 —(CH₂)₃— —C(═O)—NH— K333 J037 T170 2316 —(CH₂)₃— —C(═O)—NH— K333 J043 T170 2317 —(CH₂)₃— —C(═O)—NH— K333 J044 T170 2318 —(CH₂)₃— —C(═O)—NH— K333 J045 T170 2319 —(CH₂)₃— —C(═O)—NH— K333 J079 T170 2320 —(CH₂)₃— —C(═O)—NH— K333 J138 T170 2321 —(CH₂)₃— —C(═O)—NH— K333 J139 T170 2322 —(CH₂)₃— —C(═O)—NH— K333 J144 T170 2323 —(CH₂)₃— —C(═O)—NH— K334 J043 T170 2324 —(CH₂)₃— —C(═O)—NH— K335 J044 T170 2325 —(CH₂)₃— —C(═O)—NH— K336 J012 T148 2326 —(CH₂)₃— —C(═O)—NH— K340 J045 T170 2327 —(CH₂)₃— —C(═O)—NH— K343 J012 T148 2328 —(CH₂)₃— —C(═O)—NH— K343 J079 T170 2329 —(CH₂)₃— —C(═O)—NH— K344 J012 T148 2330 —(CH₂)₃— —C(═O)—NH— K346 J007 T170 2331 —(CH₂)₃— —C(═O)—NH— K346 J012 T148 2332 —(CH₂)₃— —C(═O)—NH— K346 J012 T170 2333 —(CH₂)₃— —C(═O)—NH— K346 J022 T170 2334 —(CH₂)₃— —C(═O)—NH— K346 J029 T170 2335 —(CH₂)₃— —C(═O)—NH— K346 J037 T170 2336 —(CH₂)₃— —C(═O)—NH— K346 J043 T148 2337 —(CH₂)₃— —C(═O)—NH— K346 J043 T170 2338 —(CH₂)₃— —C(═O)—NH— K346 J044 T170 2339 —(CH₂)₃— —C(═O)—NH— K346 J045 T170 2340 —(CH₂)₃— —C(═O)—NH— K346 J079 T170 2341 —(CH₂)₃— —C(═O)—NH— K346 J080/J081 T148 2342 —(CH₂)₃— —C(═O)—NH— K346 J090 T148 2343 —(CH₂)₃— —C(═O)—NH— K346 J100 T148 2344 —(CH₂)₃— —C(═O)—NH— K346 J138 T148 2345 —(CH₂)₃— —C(═O)—NH— K346 J138 T170 2346 —(CH₂)₃— —C(═O)—NH— K346 J139 T170 2347 —(CH₂)₃— —C(═O)—NH— K346 J144 T148 2348 —(CH₂)₃— —C(═O)—NH— K346 J144 T170 2349 —(CH₂)₃— —C(═O)—NH— K347 J138 T170 2350 —(CH₂)₃— —C(═O)—NH— K353 J012 T148 2351 —(CH₂)₃— —C(═O)—NH— K370 J139 T170 2352 —(CH₂)₃— —C(═O)—NH— K427 J012 T148 2353 —(CH₂)₃— —C(═O)—NH— K428 J045 T170 2354 —(CH₂)₃— —C(═O)—NH— K429 J012 T148 2355 —(CH₂)₃— —C(═O)—NH— K430 J045 T170 2356 —(CH₂)₃— —C(═O)— K240 J012 T148 2357 —(CH₂)₃— —C(═O)— K240 J012 T170 2358 —(CH₂)₃— —C(═O)—O— K001 J002 T148 2359 —(CH₂)₃— —C(═O)—O— K001 J007 T170 2360 —(CH₂)₃— —C(═O)—O— K001 J012 T148 2361 —(CH₂)₃— —C(═O)—O— K002 J044 T170 2362 —(CH₂)₃— —C(═O)—O— K197 J002 T148 2363 —(CH₂)₃— —C(═O)—O— K197 J012 T148 2364 —(CH₂)₃— —C(═O)—O— K197 J012 T170 2365 —(CH₂)₃— —C(═O)—O— K197 J045 T170 2366 —(CH₂)₃— —NH— K185 J007 T148 2367 —(CH₂)₃— —NH— K185 J044 T170 2368 —(CH₂)₃— —NH—C(═O)— K005 J007 T148 2369 —(CH₂)₃— —NH—C(═O)— K005 J044 T170 2370 —(CH₂)₃— —NH—C(═O)— K007 J012 T148 2371 —(CH₂)₃— —NH—C(═O)— K007 J045 T170 2372 —(CH₂)₃— —NH—C(═O)— K008 J012 T148 2373 —(CH₂)₃— —NH—C(═O)— K008 J045 T170 2374 —(CH₂)₃— —NH—C(═O)— K009 J007 T148 2375 —(CH₂)₃— —NH—C(═O)— K009 J044 T170 2376 —(CH₂)₃— —NH—C(═O)— K011 J007 T148 2377 —(CH₂)₃— —NH—C(═O)— K011 J044 T170 2378 —(CH₂)₃— —NH—C(═O)— K013 J007 T148 2379 —(CH₂)₃— —NH—C(═O)— K013 J044 T170 2380 —(CH₂)₃— —NH—C(═O)— K051 J012 T148 2381 —(CH₂)₃— —NH—C(═O)— K051 J045 T170 2382 —(CH₂)₃— —NH—C(═O)— K200 J012 T148 2383 —(CH₂)₃— —NH—C(═O)— K200 J045 T170 2384 —(CH₂)₃— —NH—C(═O)— K204 J007 T148 2385 —(CH₂)₃— —NH—C(═O)— K204 J044 T170 2386 —(CH₂)₃— —NH—C(═O)— K208 J012 T148 2387 —(CH₂)₃— —NH—C(═O)— K208 J045 T170 2388 —(CH₂)₃— —NH—C(═O)— K212 J012 T148 2389 —(CH₂)₃— —NH—C(═O)— K212 J045 T170 2390 —(CH₂)₃— —NH—C(═O)— K262 J012 T148 2391 —(CH₂)₃— —NH—C(═O)— K262 J045 T170 2392 —(CH₂)₃— —NH—C(═O)— K263 J007 T148 2393 —(CH₂)₃— —NH—C(═O)— K263 J044 T170 2394 —(CH₂)₃— —NH—C(═O)— K266 J007 T148 2395 —(CH₂)₃— —NH—C(═O)— K266 J044 T170 2396 —(CH₂)₃— —NH—C(═O)— K272 J012 T148 2397 —(CH₂)₃— —NH—C(═O)— K272 J045 T170 2398 —(CH₂)₃— —NH—C(═O)— K293 J007 T148 2399 —(CH₂)₃— —NH—C(═O)— K293 J044 T170 2400 —(CH₂)₃— —NH—C(═O)—NH— K033 J012 T148 2401 —(CH₂)₃— —NH—C(═O)—NH— K033 J045 T170 2402 —(CH₂)₃— —NH—C(═O)—NH— K333 J007 T148 2403 —(CH₂)₃— —NH—C(═O)—NH— K333 J044 T170 2404 —(CH₂)₃— —NH—C(═O)—NH— K336 J012 T148 2405 —(CH₂)₃— —NH—C(═O)—NH— K336 J045 T170 2406 Single bond Single bond K001 J002 T170 2407 Single bond Single bond K001 J007 T148 2408 Single bond Single bond K001 J007 T170 2409 Single bond Single bond K001 J012 T148 2410 Single bond Single bond K001 J012 T170 2411 Single bond Single bond K001 J029 T148 2412 Single bond Single bond K001 J029 T170 2413 Single bond Single bond K001 J037 T148 2414 Single bond Single bond K001 J037 T170 2415 Single bond Single bond K001 J043 T148 2416 Single bond Single bond K001 J043 T170 2417 Single bond Single bond K001 J044 T148 2418 Single bond Single bond K001 J044 T170 2419 Single bond Single bond K001 J045 T148 2420 Single bond Single bond K001 J045 T170 2421 Single bond Single bond K001 J138 T148 2422 Single bond Single bond K001 J138 T170 2423 Single bond Single bond K001 J144 T148 2424 Single bond Single bond K001 J144 T170 2425 Single bond Single bond K002 J012 T148 2426 Single bond Single bond K002 J012 T170 2427 Single bond Single bond K002 J044 T148 2428 Single bond Single bond K002 J044 T170 2429 Single bond Single bond K002 J045 T170 2430 Single bond Single bond K002 J139 T148 2431 Single bond Single bond K002 J139 T170 2432 Single bond Single bond K197 J002 T148 2433 Single bond Single bond K197 J002 T170 2434 Single bond Single bond K197 J007 T148 2435 Single bond Single bond K197 J007 T170 2436 Single bond Single bond K197 J008 T148 2437 Single bond Single bond K197 J008 T170 2438 Single bond Single bond K197 J010 T148 2439 Single bond Single bond K197 J010 T170 2440 Single bond Single bond K197 J012 T170 2441 Single bond Single bond K197 J013 T148 2442 Single bond Single bond K197 J013 T170 2443 Single bond Single bond K197 J014 T148 2444 Single bond Single bond K197 J014 T170 2445 Single bond Single bond K197 J018 T148 2446 Single bond Single bond K197 J022 T148 2447 Single bond Single bond K197 J022 T170 2448 Single bond Single bond K197 J026 T148 2449 Single bond Single bond K197 J026 T170 2450 Single bond Single bond K197 J027 T148 2451 Single bond Single bond K197 J027 T170 2452 Single bond Single bond K197 J028 T148 2453 Single bond Single bond K197 J028 T170 2454 Single bond Single bond K197 J029 T148 2455 Single bond Single bond K197 J029 T169 2456 Single bond Single bond K197 J029 T170 2457 Single bond Single bond K197 J030 T148 2458 Single bond Single bond K197 J030 T170 2459 Single bond Single bond K197 J031 T148 2460 Single bond Single bond K197 J031 T170 2461 Single bond Single bond K197 J032 T148 2462 Single bond Single bond K197 J032 T170 2463 Single bond Single bond K197 J034 T148 2464 Single bond Single bond K197 J034 T170 2465 Single bond Single bond K197 J036 T148 2466 Single bond Single bond K197 J036 T170 2467 Single bond Single bond K197 J037 T148 2468 Single bond Single bond K197 J037 T170 2469 Single bond Single bond K197 J039 T148 2470 Single bond Single bond K197 J039 T170 2471 Single bond Single bond K197 J043 T148 2472 Single bond Single bond K197 J043 T170 2473 Single bond Single bond K197 J044 T148 2474 Single bond Single bond K197 J044 T170 2475 Single bond Single bond K197 J045 T148 2476 Single bond Single bond K197 J045 T170 2477 Single bond Single bond K197 J090 T148 2478 Single bond Single bond K197 J090 T170 2479 Single bond Single bond K197 J092 T148 2480 Single bond Single bond K197 J092 T170 2481 Single bond Single bond K197 J144 T148 2482 Single bond Single bond K197 J121 T148 2483 Single bond Single bond K197 J121 T170 2484 Single bond Single bond K197 J137 T148 2485 Single bond Single bond K197 J137 T170 2486 Single bond Single bond K197 J138 T148 2487 Single bond Single bond K197 J138 T170 2488 Single bond Single bond K197 J139 T148 2489 Single bond Single bond K197 J139 T170 2490 Single bond Single bond K197 J141 T148 2491 Single bond Single bond K197 J141 T170 2492 Single bond Single bond K197 J142 T148 2493 Single bond Single bond K197 J142 T169 2494 Single bond Single bond K197 J142 T170 2495 Single bond Single bond K197 J143 T148 2496 Single bond Single bond K197 J143 T170 2497 Single bond Single bond K197 J107 T148 2498 Single bond Single bond K197 J144 T170 2499 Single bond Single bond K223 J001 T164 2500 Single bond Single bond K223 J138 T148 2501 —(CH₂)₃— —C(═O)—O— K002 J001 T001 2502 —(CH₂)₃— —C(═O)—O— K002 J001 T005 2503 —(CH₂)₃— —C(═O)—O— K197 J001 T148 2504 —(CH₂)₃— —C(═O)—O— K002 J002 T148 2505 —(CH₂)₃— —C(═O)—O— K197 J002 T170 2506 —(CH₂)₃— —C(═O)—NH— K346 J002 T170 2507 —(CH₂)₃— —C(═O)—O— K002 J012 T001 2508 —(CH₂)₃— —C(═O)—O— K002 J012 T005 2509 —(CH₂)₃— —C(═O)—O— K002 J012 T148 2510 —(CH₂)₃— —C(═O)—O— K002 J012 T170 2511 —(CH₂)₂— —NH—C(═O)— K005 J012 T004 2512 —(CH₂)₃— —C(═O)—O— K002 J001 T148 2513 —(CH₂)₂— —NH—C(═O)—O— K005 J045 T181 2514 —(CH₂)₂— —NH—C(═O)— K338 J012 T148

Also, among compounds described in Table 1, compounds of the following numbers are more preferred.

Compound numbers 19, 20, 22, 27, 29, 30, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 81, 84, 85, 86, 87, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 130, 131, 132, 133, 134, 135, 136, 137, 138, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166, 167, 168, 170, 171, 172, 173, 174, 175, 176, 177, 178, 180, 181, 182, 183, 184, 185, 186, 187, 188, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 206, 210, 211, 213, 214, 217, 219, 221, 223, 225, 226, 227, 228, 229, 230, 231, 232, 237, 240, 241, 242, 243, 244, 245, 250, 253, 254, 255, 257, 258, 260, 261, 262, 263, 265, 266, 267, 268, 269, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 320, 321, 327, 328, 330, 331, 332, 333, 334, 335, 340, 342, 343, 348, 349, 350, 351, 352, 353, 359, 361, 362, 363, 364, 365, 366, 368, 369, 371, 373, 379, 381, 382, 383, 384, 385, 386, 387, 392, 393, 395, 397, 398, 399, 400, 401, 407, 409, 410, 411, 412, 413, 415, 416, 417, 418, 419, 420, 421, 422, 423, 426, 427, 429, 430, 431, 432, 433, 434, 437, 438, 439, 445, 447, 448, 449, 451, 453, 454, 455, 456, 457, 463, 465, 466, 467, 468, 469, 471, 472, 473, 474, 475, 476, 477, 478, 479, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 497, 498, 499, 501, 502, 503, 504, 509, 511, 512, 513, 515, 517, 518, 519, 520, 521, 527, 529, 530, 531, 532, 533, 534, 535, 536, 537, 539, 540, 541, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 555, 556, 557, 563, 565, 566, 567, 569, 571, 572, 573, 574, 575, 581, 583, 584, 585, 586, 587, 589, 590, 591, 593, 594, 595, 596, 597, 599, 600, 601, 602, 605, 606, 607, 608, 610, 611, 612, 613, 615, 616, 617, 618, 620, 621, 623, 624, 625, 626, 627, 628, 629, 630, 631, 634, 635, 638, 639, 641, 642, 643, 644, 645, 646, 647, 648, 651, 652, 653, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 675, 676, 677, 678, 679, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 700, 701, 702, 704, 705, 706, 707, 709, 710, 711, 712, 713, 715, 716, 717, 718, 719, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 743, 744, 745, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 773, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 852, 853, 874, 892, 893, 915, 917, 918, 919, 921, 939, 946, 998, 1000, 1001, 1002, 1007, 1008, 1014, 1015, 1054, 1055, 1056, 1059, 1061, 1063, 1065, 1067, 1069, 1071, 1073, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1083, 1085, 1089, 1090, 1091, 1092, 1093, 1095, 1096, 1097, 1098, 1099, 1103, 1104, 1106, 1110, 1112, 1113, 1115, 1117, 1118, 1120, 1121, 1127, 1129, 1130, 1131, 1132, 1134, 1137, 1140, 1143, 1146, 1151, 1152, 1153, 1155, 1156, 1158, 1159, 1161, 1165, 1166, 1167, 1168, 1170, 1178, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1289, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1420, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492, 1493, 1494, 1495, 1496, 1497, 1498, 1499, 1500, 1501, 1502, 1503, 1504, 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1527, 1528, 1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537, 1538, 1539, 1540, 1541, 1542, 1543, 1544, 1545, 1546, 1547, 1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560, 1561, 1562, 1563, 1564, 1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1583, 1584, 1585, 1586, 1587, 1588, 1589, 1590, 1591, 1592, 1593, 1594, 1595, 1596, 1597, 1598, 1599, 1600, 1601, 1602, 1603, 1604, 1605, 1606, 1607, 1608, 1609, 1610, 1611, 1612, 1613, 1614, 1615, 1616, 1617, 1618, 1619, 1620, 1621, 1622, 1623, 1624, 1625, 1626, 1627, 1628, 1629, 1630, 1631, 1632, 1633, 1634, 1635, 1636, 1637, 1638, 1639, 1640, 1641, 1642, 1643, 1644, 1645, 1646, 1647, 1648, 1649, 1650, 1651, 1652, 1653, 1654, 1655, 1656, 1657, 1658, 1659, 1660, 1661, 1662, 1663, 1664, 1665, 1666, 1667, 1668, 1669, 1670, 1671, 1672, 1673, 1674, 1675, 1676, 1677, 1678, 1679, 1680, 1681, 1682, 1683, 1684, 1685, 1686, 1687, 1688, 1689, 1690, 1691, 1692, 1693, 1694, 1695, 1696, 1697, 1698, 1700, 1701, 1702, 1703, 1704, 1705, 1706, 1707, 1708, 1709, 1710, 1711, 1712, 1713, 1714, 1715, 1716, 1717, 1718, 1719, 1720, 1721, 1722, 1723, 1724, 1725, 1726, 1727, 1728, 1729, 1730, 1731, 1732, 1733, 1734, 1735, 1736, 1737, 1738, 1739, 1740, 1741, 1742, 1743, 1744, 1745, 1746, 1747, 1748, 1749, 1750, 1751, 1752, 1753, 1754, 1755, 1756, 1757, 1758, 1759, 1760, 1761, 1762, 1763, 1764, 1765, 1766, 1767, 1768, 1769, 1770, 1771, 1772, 1773, 1774, 1775, 1776, 1777, 1778, 1779, 1780, 1781, 1782, 1783, 1784, 1785, 1786, 1787, 1788, 1789, 1790, 1791, 1792, 1793, 1794, 1795, 1796, 1797, 1798, 1799, 1800, 1801, 1802, 1803, 1804, 1805, 1806, 1807, 1808, 1809, 1810, 1811, 1812, 1813, 1814, 1815, 1816, 1817, 1818, 1819, 1820, 1821, 1822, 1823, 1824, 1825, 1826, 1827, 1829, 1830, 1831, 1832, 1833, 1834, 1835, 1836, 1837, 1838, 1839, 1840, 1841, 1842, 1843, 1844, 1845, 1846, 1847, 1848, 1849, 1850, 1851, 1852, 1853, 1854, 1855, 1856, 1857, 1858, 1859, 1860, 1861, 1862, 1863, 1864, 1865, 1866, 1867, 1868, 1869, 1870, 1871, 1872, 1873, 1874, 1875, 1876, 1877, 1878, 1879, 1880, 1881, 1882, 1883, 1884, 1885, 1886, 1887, 1888, 1889, 1890, 1891, 1892, 1893, 1894, 1895, 1896, 1897, 1898, 1899, 1900, 1901, 1902, 1903, 1904, 1905, 1906, 1907, 1908, 1909, 1910, 1911, 1912, 1913, 1914, 1915, 1916, 1917, 1918, 1919, 1920, 1921, 1922, 1923, 1924, 1925, 1926, 1927, 1928, 1929, 1930, 1931, 1932, 1933, 1934, 1935, 1936, 1937, 1938, 1939, 1940, 1941, 1942, 1943, 1944, 1945, 1946, 1947, 1948, 1949, 1950, 1951, 1952, 1953, 1954, 1955, 1956, 1957, 1958, 1959, 1960, 1961, 1962, 1963, 1964, 1965, 1966, 1967, 1968, 1969, 1970, 1971, 1972, 1973, 1974, 1975, 1976, 1977, 1978, 1979, 1980, 1981, 1982, 1983, 1984, 1985, 1986, 1987, 1988, 1989, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2029, 2030, 2031, 2032, 2033, 2034, 2035, 2036, 2037, 2038, 2039, 2040, 2041, 2042, 2043, 2044, 2045, 2046, 2047, 2048, 2049, 2050, 2051, 2052, 2053, 2054, 2055, 2056, 2057, 2058, 2059, 2060, 2061, 2062, 2063, 2064, 2065, 2066, 2067, 2068, 2069, 2070, 2071, 2072, 2073, 2074, 2075, 2076, 2077, 2078, 2079, 2080, 2081, 2082, 2083, 2084, 2085, 2086, 2087, 2088, 2089, 2090, 2091, 2092, 2093, 2094, 2095, 2096, 2097, 2098, 2099, 2100, 2101, 2102, 2103, 2104, 2105, 2106, 2107, 2108, 2109, 2111, 2112, 2113, 2114, 2115, 2116, 2117, 2118, 2119, 2121, 2122, 2123, 2124, 2125, 2128, 2129, 2130, 2131, 2132, 2133, 2134, 2135, 2136, 2137, 2138, 2139, 2140, 2143, 2144, 2145, 2146, 2147, 2148, 2149, 2150, 2151, 2152, 2153, 2154, 2155, 2156, 2157, 2158, 2159, 2160, 2161, 2162, 2163, 2164, 2166, 2167, 2168, 2169, 2170, 2171, 2172, 2173, 2174, 2175, 2176, 2177, 2178, 2179, 2180, 2181, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2190, 2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198, 2199, 2200, 2201, 2202, 2203, 2204, 2205, 2206, 2207, 2208, 2209, 2210, 2211, 2212, 2213, 2214, 2215, 2216, 2217, 2218, 2219, 2220, 2221, 2222, 2223, 2224, 2225, 2226, 2227, 2228, 2229, 2230, 2231, 2232, 2233, 2234, 2235, 2236, 2237, 2238, 2239, 2240, 2241, 2242, 2243, 2244, 2245, 2246, 2247, 2248, 2249, 2250, 2251, 2252, 2253, 2254, 2255, 2256, 2257, 2258, 2259, 2260, 2261, 2262, 2263, 2264, 2265, 2266, 2267, 2268, 2269, 2270, 2271, 2272, 2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285, 2286, 2288, 2289, 2290, 2291, 2292, 2293, 2294, 2295, 2296, 2297, 2298, 2299, 2300, 2302, 2303, 2304, 2305, 2306, 2307, 2308, 2309, 2310, 2311, 2312, 2313, 2314, 2315, 2316, 2317, 2318, 2319, 2320, 2321, 2322, 2323, 2324, 2325, 2326, 2327, 2328, 2329, 2330, 2331, 2332, 2333, 2334, 2335, 2336, 2337, 2338, 2339, 2340, 2341, 2342, 2343, 2344, 2345, 2346, 2347, 2348, 2349, 2350, 2351, 2352, 2353, 2354, 2355, 2356, 2357, 2358, 2359, 2360, 2361, 2363, 2364, 2365, 2366, 2367, 2368, 2369, 2370, 2371, 2372, 2373, 2374, 2375, 2376, 2377, 2378, 2379, 2380, 2381, 2382, 2383, 2384, 2385, 2386, 2387, 2388, 2389, 2390, 2391, 2392, 2393, 2394, 2395, 2396, 2397, 2398, 2399, 2400, 2401, 2402, 2403, 2404, 2405, 2406, 2407, 2408, 2409, 2410, 2411, 2412, 2413, 2414, 2415, 2416, 2417, 2418, 2419, 2420, 2421, 2422, 2423, 2424, 2425, 2426, 2427, 2428, 2429, 2430, 2431, 2433, 2434, 2435, 2436, 2437, 2438, 2439, 2440, 2441, 2442, 2443, 2444, 2445, 2446, 2447, 2448, 2449, 2450, 2451, 2452, 2453, 2454, 2455, 2456, 2457, 2458, 2459, 2460, 2461, 2462, 2463, 2464, 2465, 2466, 2467, 2468, 2469, 2470, 2471, 2472, 2473, 2474, 2475, 2476, 2477, 2478, 2479, 2480, 2481, 2482, 2483, 2484, 2485, 2486, 2487, 2488, 2489, 2490, 2491, 2492, 2493, 2494, 2495, 2496, 2497, 2498, 2505, 2506, 2509, 2510, 2514.

Preferred combinations of A¹, A², G¹, A³, A⁴ and G² in the formula (I) were explained above. As another method of arrangement, they can be summarized also as the following combinations 1) through 41). Not only do these combinations indicate preferred relationships among A¹, A², G¹, A³, A⁴ and G², but also the partial structures per se comprised of these as a whole are preferred substituents in the pyrrolopyrimidinone derivatives of the present invention.

1) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ is a phenylene group, the phenylene group as G¹ is preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

2) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, G¹ is a phenylene group, and the phenylene group as G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

3) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2, atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

4) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, the divalent group derived from the aromatic heterocyclic compound as G¹ is more preferably substituted with one or more substituents selected from the group consisting of substituents defined as preferred examples for the heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

5) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, when the divalent group derived from the aromatic heterocyclic compound as G¹ is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

6) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms or a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.

7) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms or a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms as a whole, but a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms as A³-A⁴-G² is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³. Also, in a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an alicyclic hydrocarbon group portion having 3 to 8 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (including a case where both are substituted).

8) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 10 carbon atoms as a whole.

9) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 10 carbon atoms as a whole, but in an aralkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon group portion having 6 to 10 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G² (including a case where both are substituted).

10) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring as a whole.

11) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring as a whole. However, in the heterocyclic substituted alkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or a heterocyclic portion is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, of G² (including a case where both are substituted).

12) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ is a phenylene group, the phenylene group as G¹ is preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

13) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, G¹ is a phenylene group, and the phenylene group as G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

14) In the formula (I), when A¹ is —(CH)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2, atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

15) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, the divalent group derived from the aromatic heterocyclic compound as G¹ is more preferably substituted with one or more substituents selected from the group consisting of substituents defined as preferred examples for the heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

16) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, when the divalent group derived from the aromatic heterocyclic compound as G¹ is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

17) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.

18) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms. However, in the cycloalkylalkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an alicyclic hydrocarbon group portion having 3 to 8 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (including a case where both are substituted).

19) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 10 carbon atoms.

20) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 14 carbon atoms. However, in the ararkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon group portion having 6 to 10 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G² (including a case where both are substituted).

21) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is preferable that A³-A⁴-G² as a whole is a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

22) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is preferable that A³-A⁴-G² as a whole is a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, in the heterocyclic substituted alkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or a heterocyclic group portion is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, of G² (including a case where both are substituted).

23) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH-G¹, and G¹ is a phenylene group, the phenylene group as G¹ is preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

24) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH-G¹, G¹ is a phenylene group, and the phenylene group as G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

25) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH-G¹, and G¹ is a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, the aromatic heterocyclic group is preferably substituted with one or more substituents selected from the group consisting of substituents defined as preferred examples for the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

26) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH-G¹, G¹ is a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, and the aromatic heterocyclic compound is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

27) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-C(═O)-G¹, G¹ is preferably a divalent group derived from a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine, and G¹ is bonded with A¹-C(═O)— through a nitrogen atom.

28) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-C(═O)-G¹, G¹ is a preferably divalent group derived from a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine, and G¹ is preferably bonded with A¹-C(═O)— through a nitrogen atom. However, the divalent group derived from the monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in the ring as G¹ is more preferably substituted with one or more substituents selected from the group consisting of substituents defined as proffered examples for the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted ring of G¹.

29) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-C(═O)-G¹, G¹ is a preferably divalent group derived from a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine, and G¹ is preferably bonded with A¹-C(═O)— through a nitrogen atom. However, when the divalent group derived from the monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in the ring as G¹ is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

30) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ is a phenylene group, the phenylene group as G¹ is preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

31) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, G¹ is a phenylene group, and the phenylene group as G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

32) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2, atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

33) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, the divalent group derived from the aromatic heterocyclic compound as G¹ is more preferably substituted with one or more substituents selected from the group consisting of substituents defined as preferred examples for the heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

34) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, when the divalent group derived from the aromatic heterocyclic compound as G¹ is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

35) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.

36) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms. However, in the cycloalkylalkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an alicyclic hydrocarbon group portion having 3 to 8 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (including a case where the both are substituted).

37) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 14 carbon atoms.

38) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 10 carbon atoms. However, in the aralkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon group portion having 6 to 10 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G² (including a case where both are substituted).

39) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is preferable that A³-A⁴-G² as a whole is a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

40) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is preferable that A³-A⁴-G² as a whole is a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, in the heterocyclic substituted alkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or a heterocyclic group portion is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, of G² (including a case where both are substituted).

41) In the formula (I), when all of A¹, A², G¹, A³, and A⁴ represent a single bond, G² is preferably a hydrogen atom or a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms.

Also, the preferred combinations of X, A¹, A², G¹, A³, A⁴ and G² in formula (I) as described in above 1) through 41) are more preferably combined with a preferred group represented by R²-A⁵-, exemplified as preferred combinations of R and A⁵, that is R²-A⁵-group in which A⁵ is a single bond and R² is a substituted or unsubstituted monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, or R²-A⁵-group in which R² is a substituted or unsubstituted aliphatic hydrocarbon group, and with a preferred group represented by R³-A⁶-, exemplified as preferred combinations of R³ and A⁶.

The pyrrolopyrimidinone derivative of the formula (I) has tautomeric forms represented by the following

[wherein A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are the same as those defined above in the formula (I).]

However, needless to say all such tautomeric forms are within the scope of the present invention.

When one or more asymmetric structures exist on atoms constituting molecules of the pyrrolopyrimidinone derivative formula (I), optically active forms of the respective asymmetric structures and their mixtures combined in an arbitrary ratio are also within the scope of the present invention.

When there exist stereochemical isomers of molecules of the pyrrolopyrimidinone derivative of formula (I), the stereochemical isomers and their combinations in any are also within the scope of the present invention.

The pyrrolopyrimidinone derivative of the formula (I) may have a basic group in its molecules. In this case, if necessary, it can be converted into pharmaceutically acceptable acid addition salts. Such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and carbonic acid; or organic acids such as acetic acid, citric acid, malic acid, oxalic acid, tartaric acid, lactic acid, maleic acid, fumaric acid, and methanesulfonic acid.

The pyrrolopyrimidinone derivative of formula (I) may have an acidic group in its molecules. In this case, when required, the acidic group may be converted into pharmaceutically acceptable salts, including non-toxic cation salts, exemplified by alkali metal ions such as Na⁺ or K⁺, alkaline earth metal ions such as Mg²⁺ or Ca²⁺, metal ions such as Al³⁺ or Zn²⁺, ammonia, and salts with an organic base such as triethylamine, ethylenediamine, propanediamine, pyrrolidine, piperidine, piperazine, pyridine, lysine, choline, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine, or N-methylglucamine.

In the formula (II), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are the same as those defined above in the formula (I), and examples thereof include the same as those exemplified in the formula (I), respectively. Also preferred examples of A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and R³ and preferred combinations of them are the same as those described for the pyrrolopyrimidinone derivative of the present invention represented in the formula (I) except those being obstacle on the chemical reaction in both of the reaction from the pyrrolopyrimidine derivative of the present invention represented by the formula (I) to the pyrrolopyrimidinone derivative of the present invention represented by the formula (I), and the reaction from the pyrrolopyrimidine derivative represented by the formula (II) to the pyrrolopyrimidinone derivative of the present invention represented by the formula (I).

In the formula (II), X¹ represents a chlorine atom, a bromine atom, an iodine atom, a C₂-C₁₀ acylthio group, a C₂-C₈ alkoxymethylthio group, a C₁-C₈ alkyl group or a C₁-C₈ arylsulfonyloxy group, but an explanation will be given below of the case where X¹ represents a chlorine atom, a bromine atom, an iodine atom, or a C₁-C₈ alkyl or arylsulfonyloxy group. When X¹ represents a C₁-C₈ alkyl or arylsulfonyloxy group, examples of the C₁-C₈ alkyl or arylsulfonyloxy group include sulfonyloxy group consisting optionally substituted C₁-C₈ alkyl or aryl group and sulfonyl group, such as methylsulfonyloxy, trifluoromethylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, butylsulfonyloxy, t-butylsulfonyloxy, nonafluorobutylsulfonyloxy, phenylsulfonyloxy, p-bromophenylsulfonyloxy, p-toluylsulfonyloxy, benzylsulfonyloxy, α-phenethylsulfonyloxy and β-phenethylsulfonyloxy. Examples of such preferred X¹ include a chlorine atom, a bromine atom, an iodine atom and a trifluoromethylsulfonyloxy group. Particularly, a chlorine atom or a trifluoromethylsulfonyloxy group is more preferred.

From the compounds represented by the formula (Ic), the pyrrolopyrimidinone derivative of formula (I) of the present invention can be easily manufactured based on the technical common sense of the person skilled in the art.

In the formula (Ic), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are the same as those defined above in formula (I), and examples thereof include the same as those exemplified in formula (I), respectively.

In the formula (Ic), Q represents a C₂-C₁₀ acyl group, a C₂-C₁₀ alkoxymethyl group, or a substituted or unsubstituted benzyl group. When Q represents a C₂-C₁₀ acyl group, examples of the C₂-C₁₀ acyl group include acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, benzoyl, phenylacetyl, phenylpropionyl, cinnamoyl. When Q represents a C₂-C₁₀ alkoxymethyl, examples of the C₂-C₁₀ alkoxymethyl group include methoxymethyl, methoxyethoxymethyl, t-butoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, p-nitrobenzyl-oxymethyl, o-nitrobenzyloxymethyl and 4-methoxyphenoxymethyl. When Q represents a substituted or unsubstituted benzyl group, examples of the substituted or unsubstituted benzyl group include benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and p-cyanobenzyl. Examples of such preferred Q include 2-(trimethylsilyl)ethoxymethyl.

The pyrrolopyrimidinone derivative of the formula (I) can be prepared from pyrrolo[3,2-d]pyrimidine derivative of the formula (II) by the following synthesis (A).

Note that, the pyrrolopyrimidinone derivative represented by the formula (I) is described as (Ia) in the following synthesis and is sometimes expressed as a pyrrolo[3,2-d]pyrimidine derivative.

[wherein R^(1A) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in formula (I). R^(2A) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in formula (I). R^(3A) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R³-A⁶ in formula (I). X¹⁰ represents a chlorine atom, a bromine atom, an iodine atom, or an optionally substituted C₁-C₈ alkyl or arylsulfonyloxy group.]

In other words, the pyrrolopyrimidinone derivative Ia-A) of the present invention can be synthesized by hydrolysis of the pyrrolo[3,2-d]pyrimidine derivative (II-A). In this hydrolysis reaction, the reaction is performed by using a base such as a sodium hydroxide or a lithium hydroxide and using a solvent such as dioxane, ethanol, 2-propanol, or dimethyl sulfoxide at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (II), a pyrrolo[3,2-d]pyrimidine derivative of formula (II-B) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia) by the following synthesis.

[wherein R^(1B) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in formula (I). R^(2B) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in formula (I). R^(3B) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R³-A⁶ in formula (I). X¹⁰ has the same meaning as defined above.]

In other words, when X¹⁰ is a chlorine atom, the pyrrolopyrimidinone derivative (II-B) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B) of the present invention with phosphorus oxychloride. In the chlorination using phosphorus oxychloride, the reaction is carried out in a solvent such as acetonitrile under general chlorination reaction conditions, for example, in the presence or absence of a solvent such as triethylamine, 4-dimethylaminopyridine or dimethyl type aniline, at a temperature in a range of 0° C. to 150° C.

Also, when X¹⁰ is a trifluoromethanesulfonyloxy group, the pyrrolopyrimidinone derivative (II-B) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B) of the present invention with trifluoromethanesulfonic anhydride. In trifluoromethane sulfonyloxylation using trifluoromethane sulfonic anhydride, the reaction can be carried out together with pyridine or amines such as triethylamine in the presence or absence of a solvent such as dichloromethane at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B1) can be synthesized from the 7-cyanopyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-CN) by the following synthesis (B1).

[wherein R^(1B1) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B1) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B1) of the present invention can be synthesized by the hydrolyzing pyrrolo[3,2-d]pyrimidine derivative (Ia-CN). The hydrolysis reaction is carried out using a base such as sodium hydroxide or lithium hydroxide in a solvent such as ethanol, 2-propanol or dimethylsulfoxide in the presence or absence of hydrogen peroxide at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-B2) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-B1) by the following synthesis (B2).

[wherein R^(1B2) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in formula (I). R^(2B2) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B2) of the present invention can be synthesized by performing a Hoffmann rearrangement on the pyrrolopyrimidinone derivative (Ia-B1) of the present invention. The Hoffmann rearrangement is carried out in a solvent such as ethanol, 2-propanol, acetonitrile or water, using a reagent such as sodium hypochlorite, bromine, or benzyltrimethyl ammonium tribromide in the presence or absence of a base such as sodium hydroxide at a temperature of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B3) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B2) by the following synthesis (B3).

[wherein R^(1B3) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B3) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(3B3) represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B3) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Is-B2) of the present invention with nitrous acid or nitrite ester and performing a Sandmayer reaction. In the Sandmayer reaction using nitrous acid or nitrite ester, reagents, for example, nitrous acid, sodium nitrite, isoamyl nitrite, or t-butyl nitrite is used, and the reaction can be performed in the presence of halogenation reagents, for example hydrofluoric acid or fluoroboric acid for fluorination, for example copper chloride or carbon tetrachloride for chlorination, for example carbon tetrabromide or bromoform for bromination, and diiodomethane or iodine for iodination, in the presence or absence of an acid such as sulfuric acid or hydrochloric acid, in the presence or absence of an acid such as sulfuric acid or hydrochloric acid, by using or without using a solvent such as ethanol, acetonitrile or water, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B4) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B2) by the following synthesis (B4).

[wherein R^(1B4) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B4) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B4) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B2) of the present invention with nitrous acid or nitrite ester. The reaction using nitrous acid or nitrite ester can be performed by using nitrous acid, sodium nitrite, isoamyl nitrite, or t-butyl nitrite as a reagent, in the presence of or in the absence of an acid such as sulfuric acid or hydrochloric acid in the presence of dimethylformamide, tetrahydrofuran, ethanol or water as a solvent, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B5) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B4) by the following synthesis (B5).

[wherein R^(1B5) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B5) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B5) of the present invention can be synthesized by reacting nitric acid or nitrogen dioxide with the pyrrolopyrimidinone derivative (Ia-B4) of the present invention. The reaction using nitric acid or nitrogen dioxide can be performed by using nitric acid, nitrogen dioxide, cerium ammonium nitrate or sodium nitrite as a reagent, in the presence or absence of sulfuric acid, hydrochloric acid, acetic acid or ozone, in the presence of dichloroethane, dichloromethane, acetonitrile or water as a solvent, at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B6) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B6a) by the following synthesis (B6).

[wherein R^(1B6) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B6) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(3B6a) is a bromine atom or iodine atom, and among groups defined as R³ in the formula (I), R^(3B6) is a substituted or unsubstituted saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring, or a trimethylsilyl.]

In other words, the pyrrolopyrimidinone derivative (Ia-B6) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B6a) of the present invention with a terminal alkyne derivative represented by formula R^(3B6)—C≡C—H in the presence of a catalytic amount of palladium. The reaction with the terminal alkyne derivative using the catalytic amount of palladium is carried out using the terminal alkyne derivative together with a palladium catalyst, e.g., tetrakis(triphenylphosphine) palladium, chlorobis(triphenylphosphine) palladium, or palladium acetate, in the presence or absence of a ligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in the presence or absence of a catalytic amount of copper salts, e.g., copper iodide or copper bromide, in the presence of a base such as triethylamine, diethylamine, piperizine or pyrrolidine, using solvents such as tetrahydrofuran, dimethylformamide, and toluene, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B7) can be prepared from the pyrrolo[3,2-d] pyrimidine derivative of formula (Ia-B7a) by the following synthesis (B7).

[wherein R^(1B7) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B7) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(3B7a) is a bromine atom or an iodine atom. R^(3B7) is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring among groups defined as R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B7) of the present invention can be synthesized, in the presence of a catalytic amount of palladium, by adding a boric acid derivative [R^(3B7)—B(OR)₂, wherein R^(3B7) is the same as defined above in the synthesis (B7), and R represents a hydrogen atom or an alkyl group] to the pyrrolopyrimidinone derivative (Ia-B7a) of the present invention. That is, in the reaction with the boric acid derivative using the catalytic amount of palladium, the reaction can be performed by using, together with the boric acid derivative, a palladium catalyst, for example, chlorobis(triphenylphosphine) palladium, palladium acetate, and tris(dibenzylideneacetone)dipalladiumu-chloroform adduct in the presence or absence of a ligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in the presence of base such as potassium phosphate, sodium carbonate, potassium hydroxide, or sodium ethoxide, using a solvent such as tetrahydrofuran, dimethylformamide, 2-propanol and water, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B8) can be synthesized from the pyrrolo[3,2-d] pyrimidine derivative of formula (Ib-B8a) by the following synthesis (B8).

[wherein R^(1B8) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B8) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(3B8a) is a bromine atom or an iodine atom, and R^(3B8) is a group defined as R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B8) of the present invention can be synthesized by reacting a terminal alkene derivative upon the pyrrolopyrimidinone derivative (Ia-B8a) of the present invention in the presence of a catalytic amount of palladium. That is, in the reaction with a terminal alkene derivative using the catalytic amount of palladium, the reaction can be performed by using, together with the terminal alkene derivative, a palladium catalyst, for example, palladium chloride, palladium acetate, or tris(dibenzylideneacetone)dipalladium-chloroform adduct in the presence or absence of a ligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino) ferrocene, in the presence of a base such as a potassium phosphate, potassium carbonate or triethylamine, and using a solvent such as tetrahydrofuran, dimethylformamide or water, at a temperature in a range of 0° C. to 150° C.

Alternatively, the pyrrolopyrimidinone derivative (Ia-B8) of the present invention can also be synthesized by performing a catalytic semi-reduction or hydroboration-protonation on the pyrrolo[3,2-d]pyrimidine derivative (Ia-B6) having an alkynyl group prepared by the Synthesis (B6). For example, the catalytic semi-reduction is performed using a solvent such as methanol, ethanol or tetrahydrofuran, in the presence of a palladium catalyst, e.g., palladium-barium sulfate-quinoline, palladium-activated carbon-quinoline, under a hydrogen atmosphere, at a temperature in a range of 0° C. to 100° C. The hydroboration-protonation is performed such that hydroboratino is performed using a hydroborating reagent, e.g., 9-borabicyclo[3.3.1]nonane or dicyclohexylborane, and protonation is then performed using acetic acid. The reaction can be performed using a solvent such as tetrahydrofuran, diethylether, methylenedichloride, or toluene, at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B9) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-B9a) by the following synthesis (B9).

[wherein R^(1B9) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in formula (I). R^(2B9) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in formula (I). R^(3B9a) is a bromine atom or an iodine atom. R^(3B9) is a substituted or unsubstituted saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, substituted or unsubstituted C₁-C₁₀ alicyclic hydrocarbon group, or a vinyl group.]

In other words, the pyrrolopyrimidinone derivative (Ia-B9) of the present invention can be synthesized by reacting an organometallic reagent to the pyrrolopyrimidinone derivative (Ia-B9a) of the present invention using a catalytic amount of palladium or nickel. For example, in the reaction with the organometallic reagent using the catalytic amount of palladium or nickel, an organozinc reagent, e.g., phenylzinc chloride or an organozinc compound prepared from a Grignard reagent and zinc chloride, an organotin reagent, e.g., phenyltrimethyltin or tetramethyltin can be used. As the Grignard reagent, organometallic reagents, such as phenylbromomagnesium or n-butylbromomagnesium, can be used. Useful examples of the palladium catalyst include tetrakis(triphenylphosphine) palladium, tris(dibenzylidene-acetone)dipalladium-chloroform adduct, chloro{1,1′-bis (diphenylphosphino)ferrocene}palladium, and the like. Useful examples of the nickel catalyst include chloro{1,3-bis (diphenylphosphino)propane}nickel or nickel bromide. The reaction can be performed using a solvent such as diethylether, tetrahydrofuran or dimethylformamide, in the presence or absence of a ligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino) ferrocene, at a temperature in a range of 0° C. to 150° C.

The pyrrolopyrimidinone derivative (Ia-B9) can also be synthesized through hydrogen reduction of the pyrrolo[3,2-d]pyrimidine derivative (Ia-B6) having an alkynyl group prepared by the synthesis (B6) or the pyrrolo[3,2-d]pyrimidine derivative (Ia-B8) having an alkenyl group prepared by the synthesis (B8). The hydrogen reduction is performed using a solvent such as methanol, ethanol or tetrahydrofuran in the presence of a catalytic amount of palladium-activated carbon under a hydrogen atmosphere at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B10) can be synthesized from the pyrrolo[3,2-d] pyrimidine derivative of formula (Iz-10a) by the following synthesis (B10).

[wherein R^(1B10) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I) R^(2B10) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(3B10a) is a bromine atom or an iodine atom. R^(3B10) is a C₂-C₁₀ hydroxyl, alkoxy, N-substituted amino or N,N-disubstituted amino group.

In other words, the pyrrolopyrimidinone derivative (Ia-B10) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B10a) of the present invention with carbon monoxide in the presence of a catalytic amount of palladium. For example, the carbonyl insertion reaction using a catalytic amount of palladium is performed under a carbon monoxide atmosphere, using a palladium catalyst, e.g., tetrakis(triphenylphosphine) palladium, palladium acetate, or tris(dibenzylideneacetone)dipalladium-chloroform adduct, in the presence or absence of a ligand, e.g., triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in the presence or absence of a base, e.g., potassium carbonate, or triethylamine. A solvent such as acetonitrile, tetrahydrofuran, or dimethylformamide is used, and the reaction is carried out at a temperature ranging between 0° C. and 150° C. In this case, addition of water as a reacting agent gives a compound with a carboxy group, and addition of an alcohol gives a compound with an alkoxycarbonyl group. Addition of a primary or secondary amine gives a compound with N-substituted or N,N-disubstituted aminocarbonyl group.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B11) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-11a) by the following synthesis (B11).

[wherein R^(1B11) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B11) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(2B11a) is a bromine atom or an iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B11) of the present invention can be synthesized by reacting the pyrrolo[3,2-d]pyrimidine derivative (Ia-B11a) of the present invention under a carbon monoxide atmosphere in the presence of a reducing agent and a catalytic amount of palladium. For example, the formylation reaction using a catalytic amount of palladium is performed under the carbon monoxide atmosphere. Useful examples of the palladium catalyst include tetrakis(triphenylphosphine) palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium-chloroform adduct. The reaction is performed using a solvent such as acetonitrile, tetrahydrofuran, or dimethylformamide in the presence or absence of a ligand such as triphenylphosphine or tri(o-tolyl)phosphine or 1,1′-bis(diphenylphosphino) ferrocene in a temperature range of 0° C. to 150° C. The reaction is performed in the presence of or in the absence of a base such as potassium carbonate or triethylamine. Addition of a reducing agent such as tributyltin hydride or triethylsilane gives a compound with a formyl group, and addition of an organometallic agent such as alkyl zinc, alkyl boron or an organotin reagent give a compound with an alkylcarbonyl group.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B12) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-B12a) by the following synthesis (B12).

[wherein R^(1B12) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B12) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(3B12a) is a bromine atom or an iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B12) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B12a) of the present invention with a trifluoromethyl donating reagent. That is, in the trifluoromethylation reaction, the reaction can be performed by utilizing various methods, for example, a method using copper (I) iodide or cesium fluoride together with a trifluoromethyl donator such as sodium trifluoroacetate or trifluoromethyl acetate, a method for preparing a trifluoromethyl copper compound from a trifluoromethyl zinc compound or a trifluoromethyl cadmium compound and copper (I) bromide, or a method for preparing a trifluoromethyl copper compound from a trifluoromethyl iodide and copper powder, by using a solvent such as dimethylformamide, N-methylpyrrolidinone, hexamethylphosphoramide, acetonitrile, or pyridine, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of Formula (Ia-B13) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of Formula (Ia-B13a) by the following synthesis (B13).

[wherein R^(1B13) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B13) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I).]

The pyrrolopyrimidinone derivative (Ia-B13) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B13a) of the present invention with water in the presence of nitrous acid. That is, the hydroxylation reaction in the presence of nitrous acid is performed using sodium nitrite or isoamyl nitrite in the presence of trifluoroacetic acid or sulfuric acid. The reaction can be performed using water as a solvent in the presence or absence of a cosolvent such as acetonitrile or dimethylformamide, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B14) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-B14a) by the following synthesis (B14).

[wherein R^(1B14) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2B14) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(3B14) is a C₁-C₆ aliphatic hydrocarbon group.]

In other words, the pyrrolopyrimidinone derivative (Ia-B14) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B14a) of the present invention with water in the presence of nitrous acid. That is, the alkylthioration reaction in the presence of nitrous acid is performed using sodium nitrite or isoamyl nitrite in the presence or absence of acids such as hydrochloric acid or sulfuric acid. The reaction is carried out using dialkyldisulfide or alkanethiol as a reagent in a solvent such as acetonitrile or dimethylformamide at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives represented by (Ia-B) of the synthesis (B) or (Ib-CN) of the synthesis (B1), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-C2) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-C1) by the following synthesis (C).

[wherein R^(1C) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2C1) is a chlorine atom or a bromine atom. R^(3C) represents a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). When A⁵ is —NR²⁰¹— (R²⁰¹ is the same as defined above for R²⁰¹ in the formula (1)), R^(2C2) is as defined to exclude a fluorine atom, a chlorine atom, a bromine atom and an iodine atom from groups defined for R² in formula (I). Also, when A⁵ is a single bond, R^(2C2) is a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring in which R^(2C2) is linked to A⁵ on a nitrogen atom.

In other words, the pyrrolopyrimidinone derivatives (Ia-C2) can be synthesized by reacting the pyrrolopyrimidinone derivatives (Ia-C1) of the present invention with a primary or secondary amine. Amination using the primary or secondary amine is performed without the use of a solvent or with the use of a solvent such as dimethylsulfoxide, dimethylformamide, dioxane, tetrahydrofuran or toluene in the presence or absence of a base such as pyridine, triethylamine, diisopropylethyl-amine, 4-dimethylaminopyridine or sodium carbonate. The reaction is performed in the presence or absence of a transition metal complex catalyst prepared by mixing a palladium salt such as palladium acetate with a phosphorus ligand such as triphenylphosphine, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives represented by the formula (Ia) or (Ia-CN) of the synthesis (B1), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-D2) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-D1) by the following synthesis (D).

[wherein R^(1D) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2D1) is a chlorine atom or a bromine atom. R^(2D2) is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring. R^(3D) is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented A⁶-R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-D2) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-D1) of the present invention with, for example, a boric acid derivative represented by R^(2D2)—B(OR)₂ [in which R^(2D2) is as defined above in the synthesis (D), and R is a hydrogen atom or an alkyl group). The reaction with the boric acid derivative is performed under general Suzuki reaction conditions, for example, at a temperature in a range of 0° C. to 150° C. using a solvent such as 2-propanol and/or water in the presence of an inorganic base such as sodium carbonate, by using a catalyst such as palladium acetate, and adding a ligand such as triphenylphosphine.

Among the pyrrolo[3,2-d]pyrimidine derivatives of Formula (Ia) or (Ia-CN) prepared in the synthesis (B1), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-E2) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-E1) in the following manner shown in Synthesis (E):

[wherein R^(1E) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2E) is a chlorine atom, a bromine atom or an iodine atom. R^(3E) is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³.]

In other words, the pyrrolopyrimidinone derivative (Ia-E2) of the present invention can be synthesized by halogenation of the pyrrolopyrimidinone derivative (Ia-E1) of the present invention. The halogenation is performed using a halogenation reagent such as N-chlorosuccinic imide or N-bromosuccinic imide in the presence of a solvent such as dimethylformamide, dioxane or tetrahydrofuran at a temperature in a range of −20° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of Formula (Ia) or (Ia-CN) prepared in the synthesis (B1), a pyrrolo[3,2-d]pyrimidine derivative of formula (1a-F) given below can be synthesized from the pyrrol derivative of formula (IV-F) in the following manner shown in Synthesis (F)

[wherein R^(1F) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2F) represents, among the groups defined for R² in the formula (I), groups excluding a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and a substituted or unsubstituted heterocyclic group that is bonded with a carbon atom and a nitrogen atom of a pyrrole ring to which R^(2F) is bonded, and having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. R^(3F) is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in formula (I).]

In other words, the pyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-F) of the present invention can be synthesized by performing a cyclization reaction using formamidine or formamide on the pyrrole derivative of formula (IV-F). The cyclization reaction using formamidine can be performed by using formamidine acetate, for example, in a solvent such as 2-propanol at a temperature in a range of 0° C. to 150° C. The cyclization reaction using formamide can be performed smoothly by using a base such as formamide or sodiummethoxide, in the presence or absence of a solvent such as dimethylsulfoxide or dimethoxyethane at a temperature in a range of 0° C. to 150° C.

The pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia) or the synthesis (B1) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of the Formula (I-G) by the following synthesis (G).

[wherein R^(1G) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2G) represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^(3G) is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in formula (I). Q is an optionally substituted C₂-C₁₀ acyl group, an optionally substituted a C₂-C₈ alkoxymethyl group, or substituted or unsubstituted benzy group.]

In other words, when for example Q is an acyl group, the pyrrolopyrimidinone derivative (Ib-G) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (I-G) of the present invention with an acyl halide. The acylation reaction using the acyl halide is performed under conventional acylation reaction conditions, for example, in the presence of triethylamine or pyridine, at a temperature in a range of 0° C. to 100° C.

Also, when Q is for example an alkoxymethyl or benzyl group, the pyrrolopyrimidinone derivative (I-G) of the present invention can be synthesized by reacting the pyrrolo[3,2-d]pyrimidine derivative (I-G) of the present invention with an alkoxymethyl halide or a benzyl halide. The reaction using the alkoxymethyl halide or the benzyl halide can be performed in the presence of for example sodium hydride in a temperature range of 0° C. to 100° C.

In the thus obtained pyrrolopyrimidinone derivatives (Ib-G) according to the present invention, conversion reactions known to one skilled in the art can be performed for A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and/or R³. Such pyrrolo[3,2-d] pyrimidine derivatives (Ib-G) can be converted into the pyrrolopyrimidinone derivatives (I-G) of the present invention by performing hydrolysis under a neutral or alkaline condition when Q is an acyl group, or under an acidic condition using, for example, trifluoroacetic acid, when Q is an alkoxymethyl group, or by performing a hydrogen addition reaction when R³ is a benzyl group.

The pyrrolopyrimidinone derivatives or the present invention synthesized by the syntheses (A), (B), (C), (D), (E), (F), and (G) have easily convertible substituents, such as an alkoxycarbonyl group, an acyloxy group, or an aromatic nitro group, they can be easily converted into pyrrolopyrimidinone derivatives or the present invention respectively having a carboxy group, a hydroxy group, and an amino group by performing reactions known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present invention synthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) have a carboxy group, they can be converted into pyrrolopyrimidinone derivatives of the present invention having an alkoxycarbonyl group, a carbamoyl group, and an N-alkylcarbamoyl group by a condensation reaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the synthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) have an amino group, they can be converted into pyrrolopyrimidinone derivatives of the present invention having an acylamino group or an alkylsulfonylamino group by a condensation reaction well known to one skilled in the art.

Also, when they have an amino group, they can also be converted into pyrrolopyrimidinone derivatives of the present invention having a monoalkylamino or a dialkylamino group by a reductive alkylation reaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present invention synthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) have a hydroxy group, they can be converted into pyrrolopyrimidinone derivatives of the present invention having an acyloxy group by a condensation reaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present invention synthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) have a formyl group, they can be converted into pyrrolopyrimidinone derivatives of the present invention having an alkylaminomethyl group by a reductive alkylation reaction known to one skilled in the art.

In the synthesis of the pyrrolopyrimidinone derivative of the formula (I), the pyrrole derivatives of formula (IV-F) used as starting materials can be prepared from a 3-alkoxypropene nitrile derivative of formula (VI-H) by the following synthesis (H).

(wherein R^(1H) represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^(2H) represents, among the groups defined for R²-A⁵ in the formula (I), groups excluding a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and a substituted or unsubstituted heterocyclic group that is bonded with a carbon atom and a nitrogen atom of a pyrrole ring to which R^(2H) is bonded, and having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. R^(3H) is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in formula (I).]

In other words, aminopropenitrile derivatives (V-H) can by synthesized by reacting alkoxypropene nitriles (VI-H) with a primary amine (represented by R¹—NH₂ in which R¹ is as defined above for R¹ prepared by the synthesis (H)). The pyrrole derivatives (IV-H) can be synthesized through a reaction between the aminopropenenitrile derivatives (V-H) and methyl bromoacetate in the presence of a base, or through a cyclization reaction.

The reaction between the alkoxypropene nitrile derivatives (V-H) and the primary amine is performed using a solvent such as methanol, ethanol or 2-propanol at a temperature in a range of 0° C. to 100° C.

The reaction between the alkoxypropenenitrile derivatives (VI-H) and methyl bromoacetate is performed in the presence of a base such as sodium carbonate using a solvent such as acetonitrile at a temperature in a range of 0° C. to 150° C.

In the synthesis of the pyrrolopyrimidinone derivative of the formula (I), among the pyrrole derivatives of the formula (IV-F) used as starting materials, a pyrrole derivative having a hydrogen atom as R^(2F) can be prepared from 3-oxopropanenitrile derivatives of formula (VII-J) by the following synthesis (J)

[wherein R^(1J) represents a group which can be converted to A¹-A²-G¹-A³-A⁴-G² in the formula (I), and a group capable of withstanding a conversion reaction. R^(3J) is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in the formula (I).]

In other words, the aminopropenenitrile derivative (V-J) can be synthesized by reacting the 3-oxopropanenitrile derivative (VII-J) with a primary amine (R¹—NH₂ in which R¹ is as defined above for R¹ prepared by the synthesis (J)). The pyrrole derivatives (IV-J) can be synthesized through a reaction between the aminopropenitrile derivatives (V-J) and methyl bromoacetate in the presence of a base, or through a cyclization reaction.

The reaction between 3-oxopropanenitrile derivative (VII-J) and the primary amine is performed using a solvent such as methanol, ethanol or 2-propanol at a temperature in a range of 0° C. to 100° C.

The reaction between the aminopropenitrile derivative (VI-J) and methyl bromoacetate is performed in the presence of a base such as sodium carbonate using a solvent such as acetonitrile in a temperature range of 0° C. to 150° C.

Alternatively, in the syntheses of the pyrrolopyrimidinone derivative of the formula (I), among the pyrrole derivatives of formula (IV-F) used as starting materials, a pyrrole derivative of formula (IV-F) having a hydrogen atom as R²F can also be prepared by the following synthesis (K):

[wherein R^(1K) represents a group which can be converted to A¹-A²-G¹-A³-A⁴-G² in the formula (I), and a group capable of withstanding a conversion reaction. R^(3K) is a cyano or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in formula (I).]

In other words, the aminopropenitrile derivative (V-K) can by synthesized by reacting the 3-oxopropanenitrile derivative (VII-K) and a glycinemethylester derivative (R¹—NH—CH₂—COOCH₃ having R¹ on a nitrogen atom in which R¹ is as defined above for R¹ prepared by the synthesis (K)) The pyrrole derivative (IV-L) can be synthesized by performing cyclization of the aminopropenitrile derivative (V-K) in the presence of a base.

The reaction between the 3-oxopropanenitrile derivative (VII-K) and the glycinemethylester derivative is performed using a solvent such as acetic acid at a temperature in a range of 0° C. to 150° C.

The cyclization reaction of the aminopropenitrile derivative (V-K) is performed using a solvent such as acetonitrile or ethylene glycol dimethyl ether in the presence of a base such as 1,8-diazabicyclo[5,4,0]-7-undecene or cesium carbonate at a temperature in a range of 0° C. to 150° C.

The thus obtained pyrrolopyrimidinone derivatives of formula (I) have an inhibitory effect of GSK-3 activity, and can be advantageously used as preventive and/or therapeutic agents which are clinically applicable GSK-3 inhibitors. Diseases that can be treated by the GSK-3 activity inhibitor include diabetes, diabetic complications, atherosclerosis, hypertension, obesity, syndrome X, Alzheimer's disease, neurodegenerative diseases (AIDS encephalophy, Huntington's disease, Parkinson's disease, or ischemic attack), manic depressive psychosis, traumatic cerebrospinal injury, alopecia, inflammatory response syndrome, cancer and immunodeficiency.

Also, the pyrrolopyrimidinone derivatives of formula (I) and its pharmaceutically acceptable salts may be formed as pharmaceutical compositions together with pharmacologically acceptable carriers and/or diluents. The compositions of the present invention may be formed as various kinds of formulations to be administered orally or parenterally. The term “parenteral” as used herein includes intravenous, subcutaneous, intramuscular, percutaneous, and rectal injection or infusion techniques.

For oral administration, examples of the formulation include tablets, pills, granules, powder, solutions, suspensions, syrups, and so on.

Here, the tablet formulations can be formed by conventional methods using a pharmaceutically acceptable carrier such as a vehicle, a binding agent, a disintegrating agent, and the like. The pills, granules and powder can also be formed by conventional methods using a vehicle or the like, like the tablets. The formulations in the form of solutions, suspensions and syrups can be prepared by general methods using glycerine esters, alcohols, water, vegetable oils, and so on. The capsule formulations can be formed by filling capsules of gelatin with granules, powder or solutions.

Among formulations for parenteral administration, intravenous, subcutaneous, and intramuscular administration can take forms of injectable formulations. For injection, the compounds of the invention may be formulated in aqueous solutions such as physiological saline or in nonaqueous solutions including organic esters such as propylene glycol, polyethylene glycol, or vegetable oils.

For transdermal administration, formulations can be used in the form of ointment or cream. Ointments can be used in combination with oils or vaselin, for example. Creams can be prepared in combination with emulsifying agents, for example.

When required, these formulations can be further provided with pharmaceutically acceptable carriers such as an isotonic, a preservative, an antiseptic, a wetting agent, a buffering agent, an emulsifying agent, a dispersing agent, or a stabilizer.

Also, such a variety of formulations can be sterilized through appropriate treatments, for example, filtration using a bacteria retaining filter or combination of disinfectants.

The amount of the pyrrolopyrimidinone derivative of formula (I) and its pharmaceutically acceptable salt that may be administered may vary depending upon the kind of a disease, administration route, symptom, age, sex, body weight, and so on of the patient. Generally, a dosage for oral administration is between 0.1 and 500 mg/day/patient. A dosage for parenteral application, including intravenous, subcutaneous, intramuscular, and percutaneous injection is between 0.1 and 100 mg/day/patient.

EXAMPLES

The present invention will now be described in more detail through the following examples. However, the present invention is not limited to these examples. In the following examples, compound numbers labeled for the respective compounds correspond to the compound numbers labeled for the compounds listed in the above tables as specific examples.

Note that, with regard to data for compounds synthesized in the following examples, the term “HPLC retention time” refers to a retention time (unit: min) associated with a particular compound in HPLC analysis performed under the following analysis condition. HPLC (High performance liquid chromatography) Analysis Condition

System: Hewlett-Packard 1100 HPLC

Column: Cadenza CD-C18 (manufactured by Imtakt Co.) 100 mm×4.6 mmφ

Solvent A:

H₂O/acetonitrile=95/5 (0.05% trifluoroacetic acid)

Solvent B:

H₂O/acetonitrile=5/95 (0.05% trifluoroacetic acid)

Flow rate: 1.0 mL/min

Gradient:

0 to 1 min Solvent B: 10%, Solvent A: 90%

1 to 14 min Solvent B: 10% →100%, Solvent A: 90% →0%

14 to 16 min Solvent B: 100%, Solvent A: 0% Calculation of the purity: Area percentage at UV absorption (254 nm)

Reference Example 1 Synthesis of (cyclopropylhydroxy-methylene)methane-1,1-dicarbonitrile

A tetrahydrofuran (150 mL) suspension of sodium hydride (11.49 g) was cooled to 0° C. To the cooled suspension was added dropwise a tetrahydrofuran (50 mL) solution of malononitrile (15.8 g) over an hour. The reaction mixture was stirred at room temperature for 1 hour and cooled to 0° C. To the reaction mixture was added dropwise over 80 minutes a tetrahydrofuran (50 mL) solution of cyclopropylcarbonyl chloride (25.0 g). The reaction mixture was stirred at room temperature for 49 hours, followed by adding water (50 mL) to the reaction solution. The solvent was distilled off under reduced pressure. To the residue were added ethyl acetate (200 mL) and hydrochloric acid (270 mL, 1 mol/L), which was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (40.9 g) of the title compound. The NMR data of the compound is given below.

¹H-NMR(400 MHz, CDCl₃)δ(ppm): 1.10-1.22(m, 4H), 2.10-2.22(m, 1H), 4.27(s, 3H).

In a similar manner as described above, [(3-chloro(2-thienyl))hydroxymethylene]methane-1,1-dicarbonitrile was prepared from malononitrile and 3-chlorothiophene-2-carbonylchloride. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, CD₃OD) δ(ppm): 6.92 (d,J=5.1,1H) 7.51(d,J=5.4,1H)

ESI/MS m/e: (M⁺+H, C₈H₃ClN₂OS)

Reference Example 2 Synthesis of (cyclopropylmethoxy-methylene)methane-1,1-dicarbonitrile

A tetrahydrofuran (100 mL) suspension of sodium hydride (2.6 g) was cooled to 0° C. To the cooled suspension was added dropwise a tetrahydrofuran (60 mL) solution of crude (1-hydroxy-2-phenylmethylidene)methane-1,1-dicarbonitrile (14.5 g) over 30 minutes. The reaction mixture was stirred at room temperature for 20 minutes and cooled to 0° C. To the reaction mixture was added dropwise a tetrahydrofuran solution (40 mL) of dimethyl sulfate (13.7 g) over 1 hour. After heating for 21 hours to reflux, the reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue were added ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (100 mL), and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography on silica gel using hexane/ethyl acetate=1/3 as an eluent to obtain the title compound (6.8 g, 54%) as a light yellow solid. NMR data of the compound is given below.

¹H-NMR(400 MHz, CDCl₃)δ(ppm): 1.10-1.22(m,4H), 2.10-2.22(m,1H), 4.27(s,3H)

Reference Example 3 Synthesis of methyl 3-amino-1-{2-[(t-butoxy)carbonylamino]ethyl}-4-cyano-5-cyclopropylpyrrole-2-carboxylate

To an acetonitrile (150 mL) solution of (methoxycyclopropylmethylene)methane-1,1-dicarbonitrile (8.7 g) was added N-(2-aminoethyl) t-butyl carbaminic acid (16.3 g) and stirred at room temperature for 10 minutes. To the resultant product were added anhydrous cesium carbonate (38.5 g) and methyl bromoaccetate (11.2 mL), followed by heating for 6 hours to reflux. The reaction product was cooled to room temperature and allowed to stand. Then, the supernatant was separated by decantation and the solvent was distilled off under reduced pressure. The concentrated residue and a solid remaining after decantation were collected and ethyl acetate and water were added thereto, followed by extracting 3 times with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to obtain the title compound (17.5 g, yield 85%). The ESI/MS data of the compound are given below.

ESI/MS m/e: 349.1 (M⁺+H, C₁₇H₂₄N₄O₄)

Methyl 3-amino-1-{2-[(t-butoxy)carbonylamino}ethyl}-5-(3-chloro(2-thienyl))-4-cyanopyrrole-2-carboxylate was synthesized from [(3-chloro(2-thienyl))hydroxymethylene] methane-1,1-dicarbonitrile used as a starting material in a similar manner to that in Reference Examples 2 and 3. The ESI/MS data of the compound are given below.

ESI/MS m/e: 425.2 (M⁺+H, C₁₈H₂₁ClN₄O₄S)

Reference Example 4 Synthesis of (t-butoxy)-N-[2-(7-cyano-4-oxo-6-cyclopropyl(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)) ethyl]carboxyamide

Methyl 3-amino-1-{2-[(t-butoxy)carbonylamino]ethyl}-4-cyano-5-cyclopropylpyrrole-2-carboxylate (17.4 g) and formamidine acetate (104.1 g) were added to 2-propanol (360 mL) and heated for 45 hours to reflux. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue was added water, and the obtained solid was isolated by filtration and sufficiently washed with water. The resulting solid was recrystallized (ethanol/ethyl acetate/hexane=1/2/1) to obtain the title compound (9.8 g, yield 57%). The ESI/MS data of the compound are given below.

ESI/MS m/e: 362.1 (M⁺+H, C₁₇H₂₁N₅O₃)

(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide was prepared from methyl-3-amino-1-{2-[(t-butoxy)carbonyl-amino]ethyl}-5-(3-chloro(2-thienyl))-4-cyanopyrrole-2-carboxylate in a similar manner to that described above. ESI/MS data of the compound are given below.

ESI/MS m/e: 420.2 (M⁺+H, C₁₈H₁₈ClN₅O₃S)

Reference Example 5 Synthesis of 3-oxo-2-(3-pyridyl) propanenitrile hydrochloride

To a toluene solution (100 mL) of 3-pyridylacetonitrile (40.86 g) was added dimethylformamidedimethylacetal (123.6 g) and the mixture was heated for 4 hours to reflux. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain a brown solid. The obtained brown solid was washed with ethyl acetate, yielding 46.93 g of a colorless solid. To a tetrahydrofuran (300 mL) suspension of the reaction product (20.37 g) were added water (40 mL) and concentrated hydrochloric acid (24.50 mL) and the mixture was stirred at 50° C. for 4 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried in vacuo to obtain a crude product (30.12 g) of the title compound, which was used for the subsequent reaction without further purification. ESI/MS data of the compound are given below.

ESI/MS m/e: 147.1 (M⁺+H, C₈H₆N₂O HCl)

Reference Example 6 Synthesis of ethyl 3-{((1Z)-2-cyano-2-(3-pyridyl)vinyl)[(methoxycarbonyl)methyl]amino}propanate

To an acetic acid (30 mL) solution of ethyl 3-{[(methoxycarbonyl)methyl]amino}propanate (6.720 g) was added a crude product of 3-oxo-2-(3-pyridyl)propanenitrile (7.826 g), and the mixture was stirred at 80° C. for 2 days. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with water, and sodium carbonate was added thereto for neutralization, followed by extracting the solution with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate, which was then filtered for separation. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/3), to obtain the title compound (7.521 g, yield 83%). The ESI/MS data of the compound are given below.

ESI/MS m/e: 318.2 (M⁺+H, C₁₆H₁₉N₃O₄)

Reference Example 7

Synthesis of ethyl 3-[3-amino-2-(methoxycarbonyl)-4-(3-pyridyl)pyrrolyl]propanate

To an ethylene glycol dimethyl ether (50 mL) solution of ethyl 3-{((1Z)-2-cyano-2-(3-pyridyl)vinyl)[(methoxycarbonyl)methyl]amino}propanate (6.236 g) was added 1,8-diazabicyclo [5,4,0]-7-undecene (3.590 g), and the mixture was stirred at 60° C. overnight. The reaction solution was cooled to room temperature and neutralized with acetic acid, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/5), to obtain the title compound (4.380 g, yield 70%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 1.10-1.18(m,3H), 2.74(t,J=6.82, 2H), 3.77(s,3H), 3.99-4.07(m,2H), 4.38(t,J=6.84, 2H), 7.46(s,1H), 7.85(dd,J=5.74,J=7.94,1H), 8.36(d,J=8.08, 1H), 8.60(d,J=5.40, 1H), 8.84(s,1H).

ESI/MS m/e: 318.2(M⁺+H, C₁₆H₁₉N₃O₄)

Reference Example 8 Synthesis of (cyclopropylhydroxy-methylene)methane-1-(3-pyridyl)-1-carbonitrile

To a 500 mL branched flask was added 13.0 g of 3-pyridinacetonitrile (110 mmol) and 150 mL of tetrahydrofuran, and 44 mL of ^(n)BuLi (2.6 M solution) (114 mmol) was added dropwise thereto using a syringe with stirring at 0° C., followed by stirring at 0° C. for 30 minutes and at 40° C. for 30 minutes. While the reaction product was cooled at 0° C. with stirring, a tetrahydrofuran solution (30 mL) of 10.45 g of cyclopropanecarbonyl chloride (100 mmol) was added dropwise, and stirred at room temperature for 1 hour, followed by adding to the reaction solution 300 mL of a saturated ammonium chloride solution and separated. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layer was washed twice with 300 mL of saturated brine. The organic layer was dehydrated and dried over magnesium sulfate, filtered and concentrated to obtain 18.25 g of concentrated residue. To the concentrated residue was added 30 mL of acetonitrile and an insoluble portion was filtered off, followed by washing with 20 mL of acetonitrile to obtain a crude product of the title compound (5.17 g, 28%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 0.64(m,4H), 2.24(m,1H) 2.50(brds,1H), 7.70(dd,J=5.4 Hz,J=8.6 Hz,1H), 8.11(d,J=5.4 Hz,1H), 8.21(d,J=8.6 Hz,1H), 9.12(brds,1H).

ESI/MS m/e: 187.1(M⁺+H, C₁₁H₁₀N₂O)

Reference Example 9 Synthesis of (cyclopropyl-p-toluene-sulfonyloxymethylene)methane-1-(3-pyridyl)-1-carbonitrile

A 200 mL branched flask were charged with 4.51 g of (cyclopropylhydroxymethylene)methane-1-(3-pyridyl)-1-carbonitrile (24.3 mmol) and 9.14 g of p-toluene sulfonic anhydride (28 mmol), and 100 mL of dichloromethane was added thereto, followed by adding 4.8 mL of triethylamine (34.5 mmol) dropwise with stirring the reaction mixture at room temperature, and stirring at room temperature for 2 hours. After the completion of the reaction, 50 mL of water was added to the reaction solution and separated. The aqueous layer was extracted with 20 mL of dichloromethane. The organic layer was washed once with 50 mL of saturated sodium hydrogen carbonate solution and twice with 50 mL of water. The organic layer was dehydrated and dried over magnesium sulfate, filtered and concentrated to obtain a crude product (8.47 g, 100%) of the title compound. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(270 MHz, CDCl₃)δ(ppm): 1.10-1.32(m,4H), 2.40(s,3H) 2.15-2.42(m,1H), 7.05(m,3H), 7.40(m,2H), 7.60(m,1H), 8.40(m,2H).

ESI/MS m/e: 341.0(M⁺+H, C₁₈H₁₆N₂O₃S)

Reference Example 10 Synthesis of ethyl 3-amino-4-(3-pyridyl)-5-cyclopropylpyrrole-2-carboxylate

A 200 mL branched flask was charged with 7.764 g of (cyclopropyl-p-toluenesulfonyloxymethylene)methane-1-(3-pyridyl)-1-carbonitrile (22.8 mmol), and 70 mL of ethanol and 35 mL of tetrahydrofuran were added thereto, followed by adding 5.08 g of diethylaminomalonate hydrochloric acid (24 mmol) with stirring the reaction mixture at 0° C., and stirring at 0° C. for 1 hour. Subsequently, 35 mL of an ethanol solution of sodium ethoxide (5.43 g, 80 mmol) was added dropwise to the reaction solution and stirred at 0° C. for 1 hour. After the completion of the reaction, the solvent was concentrated under reduced pressure and concentrated. To the residue were added 150 mL of water and ethyl 100 mL of acetate for extraction. The aqueous layer was extracted with 50 mL of ethyl acetate. The organic layer was washed once with 100 mL of water and three times with 50 mL of saturated brine solution. The organic layer was dehydrated and dried over magnesium sulfate, filtered and concentrated to obtain 3.90 g of a crude product, which was then purified by column chromatography (silica gel 100 g; using 4:1 to 0:1 hexane/ethyl acetate as an eluent) to obtain the title compound (1.074 g, yield 17%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR (270 MHz, CDCl₃) δ(ppm): 0.60-0.95(m,4H) 1.30(m,1H), 1.36(t,J=7.0 Hz,3H), 4.15(q,J=7.0 Hz,2H), 4.35(brds,2H), 7.15(m,1H), 7.75(m,1H), 8.50(m,1H), 8.75(s,1H).

ESI/MS m/e: 272.1(M⁺+H, C₁₅H₁₇N₃O₂)

Reference Example 11 Synthesis of N-{2-[4-chloro-6-(3-chloro(2-thienyl))-7-iodopyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A 3.0 mL phosphorus oxychloride solution of N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide (333 mg) was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, and excess phosphorus oxychloride was distilled off under reduced pressure. The residue was dried in vacuo to obtain a crude product of the title compound, which was used for the subsequent reaction without further purification. The ESI/MS data of the compound are given below.

ESI/MS m/e: 535.2(M⁺+H, C₁₄H₈Cl₂F₃IN₄OS)

Reference Example 12 Synthesis of N-{2-[7-bromo-4-chloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A crude product of the title compound was prepared from N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide in a similar manner to that described in Reference Example 11. The ESI/MS data of the compound are given below.

ESI/MS m/e: 489.0(M⁺+H, C₁₄H₈BrCl₂F₃N₄OS)

Reference Example 13 Synthesis of N-{2-[4,7-dichloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A crude product of the title compound was prepared from N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide in a similar manner to that described in Reference Example 11. The ESI/MS data of the compound are given below.

ESI/MS m/e: 443.4(M⁺+H, C₁₄H₈Cl₃F₃N₄OS)

Reference Example 14 Synthesis of N-(2-{7-[(1E)-1-aza-2-(dimethylamino)vinyl]-4-chloro-6-(3-chloro(2-thienyl)) pyrrolo[3,2-d]pyrimidin-5-yl}ethyl)(4-fluorophenyl) carboxyamide

N-(6-(3-chloro(2-thienyl))-5-{2-[(4-fluorophenyl) carbonylamino]ethyl}-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide (1.09 g) was used to obtain a crude product (0.87 g) of the title compound in the same way as Reference Example 11. NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 2.81(brs,1H), 2.97(brs,1H), 3.28(s,2H), 3.37-3.45(m,2H), 7.17-7.27(m,3H), 7.55-7.68(m,2H), 7.86(d,J=5.4, 1H), 8.31-8.38(m,1H), 8.61(s,1H), 8.75(s,1H).

ESI/MS m/e: 505.4(M⁺+H, C₂₂H₁₉Cl₂FN₆OS)

Example 1 Synthesis of 5-{2-[(t-butoxy)carbonylamino]ethyl}-6-{3-chloro(2-thienyl)}-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamide (Compound No: 950)

(t-butoxy)-N-{2-[6-{3-chloro(2-thienyl)}-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (3.0 g) was dissolved in ethanol (100 mL), and a 5M aqueous sodium hydroxide solution (20 mL) was added thereto. A 30% hydrogen peroxide solution (30 mL) was added to the reaction mixture over 20 minutes with stirring. After stirring at 45 to 50° C. for 24 hours, 30% hydrogen peroxide solution (20 mL) was added to the reaction solution, stirred at 45 to 50° C. for 24 hours, concentrated and neutralized with 1 M hydrochloric acid, to obtain a white precipitate. The precipitate was filtered, washed, and dried under reduced pressure to obtain the title compound (2.68 g, yield 86%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=7.2 (min)

¹H-NMR (270 MHz, DMSO-d₆)δ(ppm): 1.26(s,9H), 3.2-3.5(m,2H), 3.8-4.0(m,1H), 4.4-4.6(m,2H), 6.5-6.6(m,1H), 7.17(d,1H,J=4.6 Hz), 7.2-7.3(m,1H), 7.91(d,1H,J=5.4 Hz),8.0-8.1(m,1H), 12.4-12.5(m,1H).

ESI/MS m/e: 438.3(M⁺+H, C₁₈H₂₀ClN₅O₄S

Example 2 Synthesis of 5-{2-[(t-butoxy)carbonylamino]ethyl}-6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamide (Compound No: 898)

The title compound was prepared from (t-butoxy)-N-{2-[6-cyclopropyl-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide in a similar manner to that described in Example 1. The ESI/MS data of the compound are given below.

ESI/MS:m/e 362.1(M⁺+H, C₁₇H₂₃N₅O₄)

Example 3 Synthesis of N-[2-[7-amino-6-(3-chloro (2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)] ethyl} (t-butoxy)carboxyamide (Compound No: 959)

5-{2-[(t-butoxy)carbonylamino]ethyl}-6-(3-chloro(2-thienyl))₄-oxo-3-hydropyrrolo[3,2-d]pyrimidine-7-carboxyamide (110 mg) was suspended in a 1 M aqueous sodium hydroxide solution (7.5 mL), and benzyltrimethylammonium tribromide (135 mg) was added thereto and the mixture was stirred for 1.5 hours. 1 M hydrochloric acid was added to the reaction mixture to acidify the reaction system, and then washed with ethyl acetate. The aqueous layer was made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (15 g) using 1:1 to 0:1 hexane:ethyl acetate as an eluent to obtain the title compound (72 mg, yield 70%). The NMR data and ESI/MS data of the compound are given below.

HPLC retention time=6.4 (min)

¹H-NMR (270 MHz,CDCl₃)δ(ppm): 1.32(s,9H), 3.3-3.5(m,2H), 4.3-4.5(m,2H), 4.9-5.0(m,1H), 7.11(d,1H,J=5.4 Hz), 7.54(d,1H,J=5.4 Hz), 7.79(brs,1H), 10.0-10.1(m,1H).

ESI/MS m/e: 410.3(M⁺+H, C₁₇H₂₀ClN₅O₃S)

Example 4 Synthesis of N-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (Compound No: 903)

The title compound was prepared from 5-{2-[(t-butoxy)carbonylamino]ethyl}-6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamide in a similar manner to that described in Example 3. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(270 MHz, CDCl₃)δ(ppm): 1.34(s,9H), 0.8-1.2(m,5H), 3.4(brs,2H), 3.5-3.6(m,3H), 4.5-4.6(m,2H), 5.6(brs,1H), 7.8(brs,1H)

ESI/MS m/e: 334.1(M⁺+H, C₁₆H₂₃N₅O₃)

Example 5 Synthesis of (t-butoxy)-N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No: 945)

To 30 mg of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide, 1 ml of bromoform was added, followed by adding 50 μl of isoamyl nitrite. After stirring at 70° C. for 4 hours, saturated brine was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by subjecting to thin layer chromatography on silica gel using ethyl acetate as a developing solvent to obtain the title compound (15 mg, yield 43%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.5 (min)

¹H-NMR(270 MHz,CDCl₃)δ(ppm): 1.31(s,9H), 3.3-3.5(m,2H) 4.2-4.3(m,1H), 4.5-4.7(m,1H), 4.7-4.9(m,1H), 7.13(d,1H,J=5.7 Hz), 7.60(d,1H,J=5.4 Hz), 7.94(d,1H,J=3.0 Hz).

ESI/MS m/e 475.2(M⁺+H, C₁₇H₁₈BrClN₄O₃S)

Example 6 Synthesis of (t-butoxy)-N-{2-[7-bromo-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)] ethyl}carboxyamide (Compound No: 2511)

The title compound was prepared from N-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide in a similar manner to that described in Example 5. The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.5 (min)

1H-NMR(270 MHz, CDCl₃)δ(ppm): 1.31(s,9H), 1.1-1.3(m,5H), 3.5-3.9(m,3H), 4.5-4.9(m,2H), 5.1-5.3(brs,1H), 7.9(s,1H)

ESI/MS m/e: 397.1(M⁺+H, C₁₆H₂₁BrN₄O₂S)

Example 7 Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No: 946)

To 1 g of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide, 7 mL of diiodomethane was added, followed by adding 822 μl of isoamyl nitrite. After stirring at 70° C. for 4 hours, saturated brine was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by subjecting to chromatography on silica gel (using 5:1 to 0:1 hexane/ethyl acetate as an eluent), to yield the title compound (694 g, yield: 55%). NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.6 (min)

¹H-NMR(270 MHz,CDCl₃)δ(ppm):1.32(s,9H), 3.3-3.5(m,2H), 4.2-4.35(m,1H), 4.6-4.75(m,1H), 4.8-5.0(m,1H), 7.14(d,1H,J=5.4 Hz), 7.59(d,1H,J=5.7 Hz), 7.95-8.05(m,1H).

ESI/MS m/e 521.3(M⁺+H, C₁₇H₁₈ClIN₄O₃S

Example 8 Synthesis of (t-butoxy-N-{2-[7-iodo-6-cyclopropyl]-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)}Ethyl)carboxyamide (Compound No: 896)

The title compound was prepared from N-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide in a similar manner to that described in Example 7. The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.7 (min)

¹H-NMR(270 MHz, CDCl₃)δ(ppm): 1.31(s,9H), 1.0-1.3(m,5H), 3.5-3.8(m,3H), 4.7-4.9(m,2H), 5.2-5.3(brs,1H), 7.9(s,1H)

ESI/MS m/e: 445.4(M⁺+H, C₁₆H₂₁IN₄O₃)

Example 9 Synthesis of (t-butoxy)-N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No: 944)

To 20 mg of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide, 2 ml of carbon tetrachloride was added, followed by adding 34 μl of isoamyl nitrite. After refluxing for 40 hours, saturated brine was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by subjecting to thin layer chromatography on silica gel (using ethyl acetate as a developing solvent) to obtain the title compound (5 mg, yield: 24%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.4 (min)

¹H-NMR(270 MHz, CDCl₃)δ(ppm): 1.32(s,9H), 3.3-3.5(m,2H), 4.15-4.4(m,1H), 4.6-4.75(m,1H), 4.8-4.95(m,1H), 7.13(d,1H,J=5.4 Hz), 7.60(d,1H,J=5.4 Hz), 7.98(brs,1H).

ESI/MS m/e 429.4(M⁺+H, C₁₇H₁₈Cl₂N₄O₃S)

Example 10 Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 943)

To 15 mg of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide, 2 mL of tetrahydrofuran was added, followed by adding 50 μl of isoamyl nitrite. After stirring at 50° C. for 3 hours, saturated brine was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by subjecting to thin layer chromatography on silica gel (developing solvent: ethyl acetate) to obtain the title compound (8 mg, yield 55%). The NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.4 (min)

¹H-NMR(270 MHz,CDCl₃) δ(ppm): 1.31(s,9H), 3.3-3.5(m,2H) 4.4-4.6(m,2H), 5.01(brs,1H), 6.66(s,1H), 7.07(d,1H, J=5.4 Hz), 7.49(d,1H, J=5.1 Hz), 7.93(brs, 1H), 11.2-11.3(m,1H).

ESI/MS m/e 395.2(M⁺+H, C₁₇H₁₉ClN₄O₃S)

Example 11 Synthesis of 5-(2-aminoethyl)-6-(3-chloro (2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (Compound No. 206)

(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (331 mg) was dissolved in a mixed solution of methanol (0.5 mL) and 1,4-dioxane (5.0 mL), and hydrochloric acid/1,4-dioxane solution (4 mol/L, 0.64 mL) was added and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain the title compound (334 mg in a quantitative yield). The ESI/MS data of the compound are given below.

ESI/MS m/e: 421.2 (M⁺+H, C₁₂H₁₀ClN₄OS HCl)

Example 12 Synthesis of 5-(2-aminoethyl)-7-bromo-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (Compound No. 205)

The title compound was prepared from (t-butoxy)-N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide in a similar manner to that described in Example 11. The ESI/MS data of the compound are given below.

ESI/MS m/e: 375.0(M⁺+H, C₁₂H₁₀BrClN₄OS HCl)

Example 13 Synthesis of 5-(2-aminoethyl)-7-chloro-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (Compound No. 204)

The title compound was prepared from (t-butoxy)-N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide in a similar manner to that described in Example 11. The ESI/MS data of the compound are given below.

ESI/MS m/e: 329.4(M⁺+H, C₁₂H₁₀Cl₂N₄OS HCl)

Example 14 Synthesis of N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide (Compound No. 320)

To a tetrahydrofuran (5.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (259 mg) was added trifluoroacetic anhydride (595 mg), and triethylamine (1.2 mL) was added slowly dropwise. The reaction mixture was stirred at room temperature for 2 hours, and methanol was added to stop the reaction. The solvent was distilled off under reduced pressure. To the residue were added water and ethyl acetate, which was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure. The residue was dried under reduced to obtain a crude product (365 mg) of the title compound. The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.1(min)

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 3.45(m,2H), 4.16(m,1H) 4.61(m,1H), 7.30(m,1H), 7.93(m,1H), 8.02(m,1H), 9.37 (m,1H), 12.29 (brs,1H).

ESI/MS m/e: 517.2(M⁺+H, C₁₄H₉ClF₃₁N₄O₂S)

Example 15 Synthesis of N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide (Compound No. 319)

The title compound was prepared from 5-(2-aminoethyl)-7-bromo-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride in a similar manner to that described in Example 14. The ESI/MS data of the compound are given below.

ESI/MS m/e: 471.1(M⁺+H, C₁₄H₉BrClF₃N₄O₂S)

Example 16 Synthesis of N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide (Compound No. 318)

The title compound was prepared from 5-(2-aminoethyl)-7-chloro-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride in a similar manner to that described in Example 14. The ESI/MS data of the compound are given below.

ESI/MS m/e: 425.4(M⁺+H, C₁₄H₉Cl₂F₃N₄O₂S)

Example 17 Synthesis of N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(4-fluorophenyl)carboxyamide (Compound No. 344)

To an N,N-dimethylacetamide (2.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (33 mg) was added 4-fluorobenzoylchloride (23 mg), and the mixture was stirred at room temperature for a short time, followed by adding triethylamine (0.2 mL) and stirring at room temperature for 2 hours. To the reaction solution was added water (0.2 mL), and the solution was stirred again at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (22 mg, yield 55%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.1 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 3.52(m,2H), 4.24(m,1H), 4.63(m,1H), 7.19-7.26(m,3H), 7.70-7.74(m,2H), 7.88-7.92(m,2H), 8.45(m,1H), 12.24(brs,1H).

ESI/MS m/e: 543.4(M⁺+H, C₁₉H₁₃ClFIN₄O₂S)

Example 18 Synthesis of 6-(3-chloro(2-thienyl))-7-iodo-5-[2-(quinazolin-4-ylamino)ethyl]-3-hydropyrrolo [3,2-d]pyrimidin-4-one (Compound No. 81)

To an N,N-dimethylacetamide (2.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (36 mg) and 4-chloroquinazoline (10 mg), was added triethylamine (16 mg) and the mixture was stirred at 70° C. for 2 hours. Triethylamine (32 mg) was further added to the reaction mixture and stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and purified by fraction HPLC to obtain the title compound (21 mg, yield 49%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time: 6.9 (min)

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 3.95(m,2H), 4.48(m,1H) 4.87(m,1H), 7.12(m,1H), 7.71-7.82(m,3H), 7.87(brs,1H), 8.00(t,J=7.7,1H), 8.18(d,J=8.3,1H), 8.60(s,1H), 9.91(brs,1H), 12.24(brs,1H). ESI/MS m/e: 549.4(M⁺+H, C₂₀H₁₄ClIN₆OS)

Example 19 Synthesis of N-(5-{2-[(t-butoxy)carbonylamino] ethyl}-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide (Compound No. 962)

To a tetrahydrofuran solution (39 mL) of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (1.60 g) was added triethylamine (2.7 mL), and cooled to 0° C., followed by adding trifluoroacetic anhydride (1.35 mL) slowly dropwise. The reaction mixture was stirred at room temperature for 1 hour, and saturated brine was added dropwise to stop the reaction. Ethyl acetate was added to the reaction solution for extraction. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain the title compound (1.97 g, a quantitative yield) as a light yellow solid. The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.7 (min)

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 1.26(s,9H), 3.13-3.26(m,2H), 4.11(brs,1H), 4.49(brs,1H), 6.60-6.73(m,1H), 7.23(d,J=5.4,1H), 7.88(s,1H), 7.95(d,J=5.4,1H), 10.86(s,1H), 12.21(brs,1H).

ESI/MS m/e: 506.4(M⁺+H, C₁₉H₁₉ClF₃N₅O₄S)

Example 20 Synthesis of N-[5-(2-aminoethyl)-6-(3-chloro (2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]-2,2,2-trifluoroacetamide hydrochloride (Compound No. 207)

A methanol solution (13 mL) of N-(5-{2-[(t-butoxy) carbonylamino]ethyl}-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide (1.97 g) was cooled to 0° C. and added was 4 mol/L hydrochloric acid/1,4-dioxane solution (26 mL), followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure, yielding a crude product (1.73 g) of the title compound. The ESI/MS data of the compound are given below.

ESI/MS m/e: 406.3(M⁺+H, C₁₄H₁₁F₃N₅O₂S.HCl)

Example 21 Synthesis of N-(6-(3-chloro(2-thienyl))-5-{2-[(4-fluorophenyl)carbonylamino]ethyl}-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide (Compound No. 345)

N-[5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]-2,2,2-trifluoro-acetamide crude product (1.73 g) in pyridine (39 mL) was cooled to 0° C., and 4-fluorobenzoylchloride (0.92 mL) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction solution was added water (40 mL), stirred at room temperature for 1 hour, and to stop the reaction. Brine was added until the reaction solution was saturated, and extraction with ethyl acetate was performed. The organic layer was washed with a mixed solution of saturated brine and 1 mol/L of hydrochloric acid (9:1), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure and purified by column chromatography on silica gel using 1/2 hexane/ethyl acetate and then using ethyl acetate only as eluents to obtain the title compound (1.60 g, 78% yield for 2 steps). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.3 (min)

¹H-NMR(400 MHz, DMSO-d₆)δ(PPM): 3.49-3.58(m,2H) 4.34(brs,1H), 4.66(brs,₁₁H), 7.16(d,J=5.4,1H), 7.19(t,J=7.1, 2H), 7.65-7.75(m,2H), 7.83(d,J=5.4,1H), 7.88(s,1H), 8.40-8.50(m,1H), 10.85(s,1H), 12.25(brs,1H).

ESI/MS m/e: 528.4 (M⁺+H, C₂₁H₁₄ClF₄N₅O₃S)

Example 22 Synthesis of (t-butoxy)-N-{2-[6-(3-chloro (2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 965)

To a tetrahydrofuran solution (10 mL) of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (0.41 g) was added triethylamine (0.69 mL), and the reaction mixture was cooled to 0° C. and benzoylchloride (0.29 mL) was added slowly dropwise. The reaction mixture was stirred at room temperature for 1 hour, and an aqueous sodium hydroxide solution (2 mol/L, 2.0 mL) was added dropwise and stirred for 18 hours to stop the reaction. Hydrochloric acid (1 mol/L, 4.0 mL) was added to the reaction solution for neutralization, brine was added thereto until the reaction solution was saturated, and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and purified by column chromatography was performed on silica gel using ethyl acetate only to obtain the title compound (0.51 g, a quantitative yield). The ESI/MS data of the compound are given below.

ESI/MS m/e: 514.4(M⁺+H, C₂₄H₂₄ClN₅O₄S)

Example 23 Synthesis of N-[5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide hydrochloride (Compound No. 208)

To a methanol solution (3.3 mL) of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (0.51 g) was added 4 mol/L hydrochloric acid/1,4-dioxane solution (6.6 mL) and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, yielding a crude product (0.47 g) of the title compound. The ESI/MS data of the compound are given below.

ESI/MS m/e: 414.3 (M⁺+H, C₁₉H₁₆ClN₅O₂.HCl)

Example 24 Synthesis of N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(4-fluorophenyl)carboxyamide (Compound No. 346)

To a dimethylacetamide solution (1.0 mL) of N-[5-(aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide (45 mg), were added 4-fluorobenzoylchloride (23.6 μL) and triethylamine (55 μL) and the mixture was stirred at room temperature for 1 hour. 2 mol/L of an aqueous sodium hydroxide solution (1.0 mL) was added dropwise, and the solution was stirred for 1 hour and stopped the reaction. 1 mol/L of hydrochloric acid (2.0 mL) was added to the reaction solution for neutralization, brine was added thereto until the reaction solution was saturated, and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and purified by fraction HPLC to obtain the title compound (25.5 mg, yield 48%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.2 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 3.50-3.70(m,2H), 4.35(brs,1H), 4.68(brs,1H), 7.12(d,J=5.4, 1H), 7.22(t,J=8.8, 2H), 7.44(t,J=7.3, 2H), 7.47-7.56(m,1H), 7.69-7.78(m,3H), 7.84(d,J=7.6, 2H), 7.89(s,1H), 8.47(t,J=5.4,1H), 9.72(s,1H), 12.22(brs,1H).

ESI/MS m/e: 536.4(M⁺+H, C₂₆H₁₉ClFN₅O₃S)

Example 25 Synthesis of N-{6-(3-chloro(2-thienyl))-4-oxo-5-[2-(quinazolin-4-ylamino)ethyl](3-hydropyrrolo[3,2-d]pyrimidin-7-yl)}benzamide (Compound No. 82)

N-[5-(aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide (45 mg) and 4-chloroquinazoline (16.5 mg) were dissolved in dimethylacetamide (2.9 mL), and triethylamine (27.7 μL) was added thereto and the mixture was stirred at 70° C. for 3 hours. Triethylamine (13.9 μL) was further added to the reaction mixture and the solution was stirred at 70° C. for 5 hours. The reaction solution was cooled to room temperature and purified by fraction HPLC, to obtain the title compound (44.3 mg, 82%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=6.4 (min)

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 3.95-4.05(m,2H), 4.52(brs,1H), 5.00(brs,1H), 7.05(d,J=5.4,1H), 7.43(t,J=7.6, 2H), 7.52(t,J=7.3,1H), 7.65(d,J=5.4, 1H), 7.70-7.85(m,5H), 8.02(t,J=7.8, 1H), 8.23(d,J=8.5, 1H), 8.61(s,1H), 9.66(s,1H), 10.17(m,1H), 12.10(brs,1H).

ESI/MS m/e: 542.4(M⁺+H, C₂₇H₂₀ClN₇O₂S)

Example 26 Synthesis of (t-butoxy)-N-[2-[6-(3-chloro (2-thienyl))-4-oxo-7-vinyl(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 966)

A nitrogen flushed flask was charged with a 0.5 M zinc chloride/tetrahydrofuran solution, and 1.0 mL of a 1.0 M vinyl magnesium bromide/tetrahydrofuran solution was added thereto with stirring, the mixture solution was stirred for 30 minutes, to obtain a suspension which was used in a subsequent reaction. To a round-bottom flask, were transferred 26 mg of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide and 12 mg of tetrakistriphenylphosphine palladium (0), followed by flushing with nitrogen and adding 2 mL dry tetrahydrofuran thereto. 600 μl of the suspension was added to the reaction mixture and the mixture was stirred at 50° C. for 8 hours, and saturated brine was added thereto and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was subjected to chromatography on silica gel (eluent: 5:1 to 0:1 hexane:ethyl acetate), to obtain the title compound (5.5 mg, yield 26%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=9.6 (min)

EMS/MS m/e 421.2(M⁺+H, C₁₉H₂₁ClN₄O₃S)

Example 27 Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-(3-hydroxy-1-prop-1-ynyl)-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 971)

A round-bottom flask was charged with 26 mg of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide, 12 mg of tetrakistriphenylphosphine palladium, 3.8 mg of copper (I) iodide and 15 μl of propargyl alcohol, followed by flushing with nitrogen, and 1 mL of dry tetrahydrofuran and 209 μl of triethylamine were added thereto. The reaction mixture was stirred at 50° C. for 5 hours, and saturated brine was added thereto and extracted with ethyl acetate. The organic layer was concentrated and subjected to column chromatography on silica gel, (developing solvent: 10 mL of toluene to 8 mL of ethyl acetate:methanol=2:1). A portion eluted by ethyl acetate/methanol was concentrated and subjected to fraction HPLC to obtain the title compound. The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=9.0 (min)

EMS/MS m/e 448.9(M+H⁺, C₂₀H₂₁ClN₄O₄S)

Example 28 Synthesis of N-{2-[7-benzo[d]furan-2-yl-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (Compound No. 1000)

A round-bottom flask was charged with 26 mg of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide, 2.2 mg of palladium acetate, triphenylphosphine, 26 mg of sodium carbonate and 16.2 mg of 2-benzofuranyl boric acid and flushed with nitrogen. 1 mL of a solution containing dimethylformamide and water mixed in a ratio of 2:1 was added to the reaction mixture and the mixture was stirred at 80° C. for 24 hours, and saturated brine was added thereto and extracted with ethyl acetate. The organic layer was concentrated and subjected to chromatography on silica gel, (developing solvent: 10 mL of toluene to 8 mL of ethyl acetate/methanol=2:1). A portion eluted by ethyl acetate/methanol was concentrated and subjected to fraction HPLC to obtain the title compound. The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=11.6 (min)

EMS/MS m/e 511.3(M+H⁺, C₂₅H₂₃ClN₄O₄S)

Example 29 Synthesis of N-{2-[6-(3-chloro-thiophen-2-yl)-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide (Compound No. 625)<

To an N,N-dimethylacetamide solution (5.0 mL) of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (173 mg) was added t-butylacetyl chloride (95 mg) and the mixture was stirred at room temperature for a short time, followed by adding triethylamine (1.0 mL) and stirring at room temperature for 2 hours. To the reaction solution was added water (1.0 mL) and further the solution was stirred at room temperature overnight. The obtained solution was extracted with ethyl acetate (10 mL×2). The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (using ethyl acetate only) to obtain the title compound (160 mg, yield: 88%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 0.84(s,9H), 1.81(d,J=3.67, 2H), 3.25-3.34(m,2H), 4.05-4.12(m,1H), 4.44-4.50(m,1H), 7.28(d,J=5.36, 1H), 7.69(t,J=5.86, 1H), 7.92(d,J=3.67, 1H), 8.00(d,J=5.36, 1H), 12.25(brs,1H).

ESI/MS m/e: 519.1(M⁺+H, C₁₈H₂₀ClIN₄O₂S)

Example 30 Synthesis of N-{2-[7-(1H-pyrazol-4-yl)-6-(3-chloro-thiophen-2-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide (Compound No. 629)

To a screw-cap vial were transferred N-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-t-butylacetylamide (26 mg), palladium acetate (2.2 mg), triphenylphosphine (5.2 mg), sodium carbonate (26 mg) and 4-(4,4,5,5,-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-1H-pyrazole (19.4 mg), and flushed with nitrogen. A 2:1 dimethylformamide:water solution (1 mL) was added to the reaction mixture and the mixture was stirred at 80° C. for 12 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The organic layer was concentrated and purified by fraction HPLC to obtain the title compound (5.2 mg, yield 23%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=10.9 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 0.85(s,9H) 1.84(d,J=1.68, 2H), 3.30-3.38(m,2H), 4.04-4.11(m,1H), 4.35-4.40(m,1H), 7.34(d,J=5.38,1H), 7.44(brs,2H), 7.76(t,J=5.60,1H), 7.93(s,1H), 8.05(d,J=5.38, 1H), 12.17(brs,1H).

EMS/MS m/e 459.3 (M+H⁺, C₂₁H₂₃ClN₆O₂S

Example 31 Synthesis of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 209) dihydrochloride

(t-butoxy)-N-{2-[6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]-ethyl}carboxyamide (1.68 g) was dissolved in methanol (10.0 mL), followed by adding 4 mol/L hydrochloric acid/1,4-dioxane solution (2.0 mL) thereto and stirring at 60° C. for 12 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain the title compound (1.64 g, a quantitative yield). The ESI/MS data of the compound are given below.

ESI/MS m/e: 371.9(M⁺+H, C₁₇H₁₄ClN₅OS 2HCl)

Example 32 Synthesis of 1-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-phenylurea (Compound No. 793)

To an N,N-dimethylformamide (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one dihydrochloride (25 mg) was added phenylisocyanate (20 mg) and the mixture was stirred at room temperature for a short time, followed by adding triethylamine (0.2 mL) and stirring at room temperature for 2 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (8 mg, yield 29%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=6.6 (min)

ESI/MS m/e: 491.04(M⁺+H, C₂₄H₁₉ClN₆O₂S

Example 33 Synthesis of 4-fluoropiperidine-1-[2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo [3,2-d]pyrimidin-5-yl]-ethyl}-carboxyamide (Compound No. 550)

To a chloroform (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo [3,2-d]pyrimidin-4-one dihydrochloride (25 mg) were added triethylamine (0.078 mL) and triphosgene (17 mg) and the mixture was stirred at room temperature for a short time, and 4-fluoropiperidine (12 mg) was added thereto followed by stirring at room temperature for 3 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (1.2 mg, yield 5%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=6.9 (min)

ESI/MS m/e: 501.41(M⁺+H, C₂₃H₂₂ClFN₆O₂S)

Example 34 Synthesis of 5-[2-(bis(cyclopropylmethyl)amino) ethyl]-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 1057)

To an N,N-dimethylformamide (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one dihydrochloride (25 mg) were added cyclopropyl aldehyde (5 mg), sodium triacetoxy borohydride (24 mg) and acetic acid (0.1 mL) and the mixture was stirred at room temperature for 10 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (10 mg, yield 36%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=5.4 (min)

ESI/MS m/e: 482.0(M⁺+H, C₂₅H₂₆ClFN₅OS)

Example 35 Synthesis of N-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide (Compound No. 626)

To an N,N-dimethylacetamide (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one dihydrochloride (25 mg) was added t-butylacetyl chloride (23 mg) and the mixture was stirred at room temperature for a short time, followed by adding triethylamine (0.2 mL) and stirring at room temperature for 2 hours. Water (0.2 mL) was added to the reaction solution and the solution was stirred again at room temperature overnight. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (19 mg, yield 72%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=7.6 (min)

ESI/MS m/e: 470.1(M⁺+H, C₂₃H₂₄ClN₅O₂S)

Example 36 Synthesis of 1-methyl-cyclohexane-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo [3,2-d]pyrimidin-5-yl]-ethyl}-carboxyamide (Compound No. 684)

To an N,N-dimethylformamide (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chlorothiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one dihydrochloride (25 mg) were added 1-methyl-cyclohexanecarboxylic acid (24 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carboxyamide hydrochloride (43 mg), N-hydroxybenzotriazole (8 mg) and triethylamine (0.2 mL) and the mixture was stirred at room temperature for 10 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (11 mg, yield 41%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=8.2 (min)

ESI/MS m/e: 496.0(M⁺+H, C₂₅H₂₆ClN₅O₂S)

Example 37 Synthesis of N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide (Compound No. 217)

To a 1,4-dioxane (6.0 mL) and methanol (1.0 mL) solution of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (356 mg) was added 4 mol/L hydrochloric acid/dioxane solution (0.75 mL) and the mixture was stirred 60° C. for 1 hour. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain crude product (370 mg). To a dimethylacetamide solution (2.0 mL) of the reaction product (26 mg) were added chloroacetyl (10 mg) and triethylamine (0.2 mL) and the mixture was stirred at room temperature for 1 hour, followed by adding water (0.2 mL) and further stirring at room temperature for 1 hour. Purification by fraction HPLC was performed to obtain the title compound (15 mg, yield 57%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=5.7 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 1.65(s,3H), 3.31-3.41(m,2H), 4.16(m,1H), 4.50(m,1H), 7.29(m,1H), 7.61(dd,J=5.12,J=8.08, 1H), 7.86(m,1H), 7.92(m,1H), 8.01(m,2H), 8.54(d,J=5.12,1H), 8.64(s,1H), 12.38(brs,1H).

ESI/MS m/e: 414.4(M⁺+H, C₁₉H¹⁶ClN₅O₂S)

Example 38 Synthesis of 6-(3-chloro(2-thienyl))-7-(3-pyridyl)-5-[2-quinazolin-4-ylamino]ethyl]-3-hydropyrrolo [3,2-d]pyrimidin-4-one (Compound No. 84)

A 4 mol/L hydrochloric acid/dioxane solution (0.75 mL) was added to a 1,4-dioxane (6.0 mL) and methanol (1.0 mL) solution of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (356 mg) and the mixture was stirred at 60° C. for 1 hour. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain a crude product (370 mg). To a dimethylacetamide (2.0 mL) solution of the reaction product (32 mg) were added 4-chloroquinazoline (13 mg) and triethylamine (16 mg) and the solution was stirred at 70° C. for 2 hours. The reaction solution was cooled to room temperature, and purification by fraction HPLC was performed to obtain the title compound (21 mg, yield 54%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=5.6 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 4.01-4.06(m,2H), 4.55(m,1H), 4.96(m,1H), 7.08(m,1H), 7.47(dd,J=4.88,J=8.04,1H), 7.72-7.78(m,3H), 7.83(m,1H), 7.90(s,1H), 8.02(t,J=7.68,1H), 8.23(d,J=8.52,1H), 8.46(d,J=5.12,1H), 8.52(s,1H), 8.67(s,1H), 10.18(m,1H), 12.30(brs,1H).

ESI/MS m/e: 500.4(M⁺+H, C₂₅H₁₈ClN₇OS)

Example 39 Synthesis of ethyl 3-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)propanate (Compound No. 35)

To an isopropyl alcohol (80 mL) solution of ethyl 3-β-amino-2-(methoxycarbonyl)-4-(3-pyridyl)pyrrolyl] propanate (4.380 g) was added formamidine acetate (7.184 g) and the mixture was stirred at 90° C. for 10 hours. The reaction solution was cooled to room temperature, and the solid was subjected to fractional filtration. The extractant was distilled off under reduced pressure. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with sodium sulfate, which was then subjected to fractional filtration. Then, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:ethanol=7:1), to obtain the title compound (0.747 g, yield 17%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=5.6 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 1.11(t,J=7.08,3H), 2.95(t,J=6.96,2H), 4.03(dd,J=6.96,J=14.28,2H), 4.63(t,J=6.84,2H), 7.81(dd,J=5.12,J=8.04,1H), 7.99(s,1H), 8.22(s,1H), 8.60(d,J=5.12,1H), 8.81(d,J=8.04,1H),9.38(s,1H), 12.29(s,1H).

ESI/MS m/e: 313.2(M⁺+H, C₁₆H₁₆N₄O₃)

Example 40 Synthesis of 3-(4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl))-N-phenylpropaneamide (Compound No. 30)

Water (0.40 mL) and a 5 M aqueous sodium hydroxide solution (0.18 mL) were added to a 1,4-dioxane (3.0 mL) solution of ethyl 3-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)propanate (91 mg) and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with acetic acid, and the resulting solid was filtered and washed with water and ethyl acetate to obtain a crude product (78 mg). 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (41 mg) and pyridine (0.2 mL) were added to a mixed solution of dichloromethane (1.0 mL) and dimethylacetamide (1.0 mL) of the reaction product (20 mg) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added aniline (20 mg) and the solution was stirred at 40° C. overnight. Methanol was added to stop the reaction, and the solvent was distilled off under reduced pressure. The residue was purified by fraction HPLC to obtain the title compound (19 mg, yield 76%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=6.1 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 2.97(t,J=6.58,2H) 4.69(t,J=6.48,2H),6.99(t,J=7.46,1H), 7.24(t,J=7.92,2H), 7.51(d,J=8.56,2H), 7.78(dd,J=5.50,J=7.94,1H), 7.99(s,1H), 8.18(s,1H), 8.57(d,J=5.40,1H), 8.78(d,J=8.04,1H), 9.36(s,1H), 9.96(s,1H), 12.30(brs,1H).

ESI/MS m/e: 360.2(M⁺+H, C₂₀H₁₇N₅O₂)

Example 41 Synthesis of 6-chloro-5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 1180)

N-chlorosuccinimide (57 mg) was added to a dimethylformamide (2.0 mL) solution of 5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (65 mg) and the mixture was stirred at room temperature for 2 hours. N-chlorosuccinimide (57 mg) was added to the reaction mixture and further the mixture was stirred at room temperature for 2 hours. Water (0.2 mL) was added to stop the reaction, and purification by fraction HPLC gave the title compound (33 mg, yield 46%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.0 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 5.82(s,2H), 7.22-7.36(m,5H), 7.72(dd,J=5.12,J=8.04,1H), 8.00(s,1H), 8.42(m,1H), 8.64(d,J=5.12,1H),9.07(s,1H), 12.41(brs,1H).

ESI/MS m/e: 337.3(M⁺+H, C₁₈H₁₃ClN₄O

Example 42 Synthesis of 7-(3-pyridyl)-4-oxo-6-cyclopropyl-3-hydropyrrolo[3,2-d]pyrimidine (Compound No. 1178)

To a 100 mL branched flask was transferred ethyl 3-amino-4-(3-pyridyl)-5-cyclopropyl pyrrole-2-carboxylate (118 mg), and isopropylalcohol (40 mL) and formamidine acetate (1.35 g) were added thereto and heated at 95° C. for 13 hours with stirring. After the completion of the reaction, the solvent was concentrated under reduced pressure. To the concentrated residue were added water (20 mL) and ethyl acetate (20 mL) for separation. The aqueous layer was extracted again with 20 mL ethyl acetate. The organic layer was washed twice with 20 mL water, dehydrated and dried with magnesium sulfate, filtered and concentrated to obtain a crude product (91 g). The crude product was washed 3 times with 1 mL methanol to yield the title compound (49 mg, yield 45%). The ESI/MS data of the compound are given below.

HPLC retention time=4.2 (min)

ESI/MS m/e: 253.1(M⁺+H, C₁₄H₁₂N₄O)

Example 43 Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(trifluoromethyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 947)

Under nitrogen atmosphere, a dry dimethylformamide suspension (10 mL) of cadmium (2.24 g) was cooled on ice with stirring, and dibromodifluoromethane (1.5 mL) was added thereto, followed by stirring at room temperature for 3 hours. Dry hexamethylphosphoramide (10 mL) was added to the reaction solution and cooled on ice, and copper (I) bromide (1.16 g) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour to obtain a copper trifluoromethyl compound suspension.

The copper trifluoromethyl compound suspension (10 mL) was added to a dry dimethylformamide solution (3 mL) of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (115 mg) and the solution was stirred at 65° C. for 6 hours. An aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by chromatography on silica gel, to obtain the title compound (35 mg, 34%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=12.1 (min)

¹H-NMR(270 MHz,CDCl₃)δ(ppm): 1.32(s,9H), 3.35-3.60(m,2H), 4.00-4.30(m,1H), 4.40-4.70(m,1H), 7.11(d,J=5.1 Hz,1H), 7.61(d,J=5.4 Hz,1H), 7.95-8.10(m,₁H).

ESI/MS m/e: 463.2 (M⁺+H, C₁₈H₁₈ClF₃N₄O₃S)

Example 44 Synthesis of 6-phenyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 2445)

An N,N-dimethylformamide/water (2:1) solution (1.0 mL) of 6-chloro-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (40 mg), phenyl boric acid (59 mg), and potassium acetate (78 mg) was subjected to deaeration, and a small amount of [1,1′-bis(diphenylphosphino)ferrocene] palladium (II) chloride dichloro-methane (1:1) complex was added thereto. The reaction mixture was heated at 140° C. for 5 minutes by using microwaves. The solvent was distilled off under reduced pressure and the residue was separated to ethyl acetate and aqueous layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried over sodium sulfate. The sodium sulfate was filtered, and solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel (0-5% methanol/ethyl acetate), and further purified by fraction HPLC to obtain the title compound (6.3 mg, yield 10%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time: 4.0 (min)

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 7.50(m,5H), 7.86(dd,J=5.7, J=8.2, 1H), 7.98(s,1H), 8.44(dt,J=1.6, J=8.2, 1H), 8.62(d,J=5.7, 1H), 8.94(s,1H).

ESI/MS m/e: 289.1(M⁺+H, C₁₇H₁₂N₄O)

Example 45 Synthesis of ethyl 4-(4-oxo-3-hydropyrrolo [3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2501)

An ethyl 4-[3-amino-2-(ethoxycarbonyl)pyrolyl] butanoate hydrochloride (20.1 g) was dissolved in dichloromethane (400 mL), and saturated aqueous sodium hydrogen carbonate (400 mL) was added thereto. The reaction mixture was vigorously stirred for 30 minutes, and two layers were separated. The aqueous layer was extracted with dichloromethane, and combined organic layer was washed with saturated brine, and dried over magnesium sulfate. The magnesium sulfate was filtered, and the solvent was distilled off under reduced pressure to obtain ethyl 4-[3-amino-2-(ethoxycarbonyl) pyrolyl]butanoate (18.0 g). This compound was dissolved in isopropylalcohol (400 mL), and formamidine acetate (9.78 g) was added thereto. This mixture was heated for 150 minutes to reflux. The solvent was distilled off under reduced pressure and the residue was separated to dichloromethane and aqueous layers. The aqueous layer was extracted with dichloromethane, and the combined organic layer was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine, which was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (13.0 mg, yield 78%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 1.14(t,J=7.1, 3H), 2.01 (pent,J=7.0, 2H), 2.21(t,J=7.5, 2H), 3.99(q,J=7.1, 2H), 4.38(t,J=6.7, 2H), 6.33(d,J=2.9, 1H), 7.41(d,J=2.9, 1H), 7.76(s, 1H), 11.86(brs,1H).

ESI/MS m/e: 250.1(M⁺+H, C₁₂H₁₅N₃O₃)

Example 46 Synthesis of ethyl 4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2502)

An N-iodosuccinimide (12.8 g) was added to a dichloromethane (350 mL) solution of ethyl 4-(4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (12.9 g), and stirred at room temperature overnight. A solid was extracted by filtration, washed with diethylether, and then dried under reduced pressure, to obtain the title compound (11.8 g, yield 61%). The filtration solution was concentrated under reduced pressure, ethyl acetate was added to the residue and vigorously stirred. The produced solid was extracted by filtration, washed with ethyl acetate and diethylether, and then dried under reduced pressure, to obtain the title compound (6.63 g, yield 34%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 1.13(t,J=7.1, 3H), 2.02 (pent,J=7.0, 2H), 2.22(t,J=7.4, 2H), 3.96(q,j=7.1, 2H), 4.39(t,J=6.7, 2H), 7.63(s, 1H), 7.85(s, 1H), 12.06(brs, 1H).

ESI/MS m/e: 376.0(M⁺+H, C₁₇H₁₈IN₃O₃)

Example 47 Synthesis of ethyl 4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2512)

The title compound was obtained by using an ethyl 4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate and 3-pyridyl boric acid in a similar manner to that described in Example 28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 1.11(t,J=7.1, 3H), 2.09 (pent,J=7.0, 2H), 2.29(t,J=7.4, 2H), 3.96(q,j=7.1, 2H), 4.45(t,J=6.7, 2H), 7.41(m, 1H), 7.93(s, 1H), 8.06(s, 1H), 8.40(m, 2H), 9.21(m, 1H), 12.10(s, br, 1H).

ESI/MS m/e: 327.0(M⁺+H, C₁₇H₁₈N₄O₃)

Example 48 Synthesis of 4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid (Compound No. 2503)

1M of aqueous lithium hydroxide solution (6.3 mL) was added to ethanol (24 mL) and water (3 mL) solution of ethyl-4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (0.78 g), and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and water (5 mL) was added to the residue. 1M hydrochloric acid was added thereto to adjust pH to 4, and a produced solid was extracted by filtration, which was dried under reduced pressure, to obtain the title compound (0.75 g, quantitative yield). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 2.07 (pent,J=7.0, 2H) 2.23(t,J=7.3, 2H), 4.46(t,J=6.7, 2H), 7.77(dd, J=4.3, J=8.2, 1H), 7.98(s, 1H), 8.24(s, 1H), 8.58(d, J=4.3, 1H), 8.79(d, J=8.2, 1H), 9.39(s, 1H), 12.12(brs, 1H), 12.24(brs, 1H)

ESI/MS m/e: 299.1(M⁺+H, C₁₅H₁₄N₄O₃)

Example 49 Synthesis of 4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)-N-benzylbutanamide (Compound No. 2292)

A diisopropylethylamine (91 μL) and benzyl amine (29 μL) were added to solution of N,N-dimethylformamide (4 mL) of 4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (40 mg). Further, O-(7-azabenzotriazol-1-yl) N,N,N′,N′-tetramethyluronium hexafluorophosphate (74 mg) was added thereto, and the mixture solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and hot water was added to the residue. An insoluble portion was filtered off, the filtration solution was concentrated under reduced pressure, purified, to obtain the title compound (11. 6 mg, yield 22%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below. The HPLC retention time: 5.1 (min)

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 2.12(m, 4H), 4.23(d, J=6.0, 2H), 4.46(t,J=6.3, 2H), 7.22(m, 3H), 7.30(m, 2H), 7.73(dd, J=5.0, J=8.2, 1H), 7.98(s, 1H), 8.19(s, 1H), 8.33(t,J=6.0, 1H), 8.56(d, J=5.0, 1H), 8.74(d, J=8.2, 1H), 9.37(brs, 1H), 12.22(brs, 1H).

ESI/MS m/e: 388.1(M⁺+H, C₂₂H₂₁N₅O₂)

Example 50 Synthesis of ethyl 4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2504)

An ethyl 4-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo [3,2-d]pyrimidin-5-yl)butanoate (1.72 g) was dissolved in dichloromethane (63 mL) by heating, and cooled to 0° C. 2 mol/L of surfuryl chloride/dichloromethane solution (7.9 mL) was added dropwise, and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and dichloromethane and saturated aqueous sodium hydrogen carbonate solution were added, and vigorously stirred. Two layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (1.89 g, quantitative yield). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm) 1.11(t,J=7.1, 3H), 2.06 (pent,J=7.0, 2H), 2.37(t,J=7.2, 2H), 3.94(q,J=7.1, 2H), 4.58(t,J=6.7, 2H), 7.51(dd, J=4.7, J=7.9, 1H), 7.93(d,J=3.0, 1H), 8.13(dt, J=1.9, J=7.9, 1H), 8.54(d,J=7, 1H), 8.94(s, 1H), 12.28(brs, 1H).

ESI/MS m/e: 361.1(M⁺+H, C₁₇H₁₇N₄O₃)

Example 51 Synthesis of 4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid (Compound No. 2505)

1M of aqueous lithium hydroxide solution (8.6 mL) was added to ethanol (25 mL) solution of ethyl-4-(6-chloro-4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (1.24 g), and stirred at room temperature overnight. 1M of hydrochloric acid (8.6 mL) was added thereto, the solvent was distilled off under reduced pressure, to obtain the title compound as a mixture (1.73 g) with lithium chloride. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 2.02(m, 2H), 2.29(t,J=7.4, 2H), 4.57(t,J=6.9, 2H), 7.58(ddd,J=0.8, J=4.9, J=8.0, 1H), 7.94(s, 1H), 8.23(ddd,J=1.5, J=2.3, J=8.0, 1H), 8.57(dd,J=1.5, J=4.9, 1H), 8.98(dd,J=0.8, J=2.3, 1H), 12.16(brs, 1H), 12.39(brs, 1H).

ESI/MS m/e: 333.1(M⁺+H, C₁₅H₁₃ClN₄O₃ LiCl)

Example 52 Synthesis of 4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)-N-(cyclohexylmethyl)butanamide (Compound No. 2264)

A cyclohexanemethylamine (27 mg) and diisopropyl-ethylamine (84 μL) were added to a solution of N,N-dimethylformamide (1 mL) of 4-(6-chloro-4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (40 mg). Further, O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (55 mg) was added thereto, and the mixture solution was stirred at room temperature for 2 hours. The reaction mixture was separated to ethyl acetate and aqueous layers. The organic layer was washed with 1 mol/L of aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine, which was dried over sodium sulfate. The sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (5% methanol/ethyl acetate) to obtain the title compound (35 mg, yield 68%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

The HPLC retention time: 7.2 (min)

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 0.09(m, 2H), 1.21(m, 3H), 1.42(m, 1H), 1.69(m, 5H), 2.16(m, 2H), 2.29(t,H=7.4, 2H), 2.95(d,J=7.0, 2H), 4.66(t,J=6.9, 2H), 7.53(ddd,J=0.9, J=5.0, J=8.0, 1H), 7.89(s, 1H), 8.22(ddd,J=1.6, J=2.2, J=8.0, 1H), 8.49(dd,J=1.6, J=5.0, 1H), 8.93(dd,J=0.9, J=2.2, 1H).

ESI/MS m/e: 428.2 (M⁺+H, C₂₂H₂₆ClN₅O₂)

Example 53 Synthesis of 4-[6-(3,4-dimethoxyphenyl)-4-oxo-7-(3-pyridyl) (3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-(cyclohexylmethyl)butanamide (Compound No. 2269)

An N,N-dimethylformamide/water (2:1) solution (2 mL) of 4-(6-chloro-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d] pyrimidin-5-yl))-N-(cyclohexylmethyl)butanamide (50 mg), 3,4-dimethoxyphenyl boric acid (64 mg), and potassium acetate (57 mg) was subjected to deaeration, followed by flushing with nitrogen gas. A small amount of [1,1′-bis(diphenylphosphino) ferrocene]palladium (II) chloride dichloro-methane (1:1) complex body was added thereto. The reaction mixture was heated at 140° C. for 30 minutes by using microwave. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (5-8% methanol/ethyl acetate), and further purified by fraction HPLC to obtain the title compound (12 mg, yield 16%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time: 8.0 (min)

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 0.85(m,2H), 1.19(m, 3H) 1.35(m, 1H), 1.66(m, 5H), 2.01(m, 2H), 2.13(t, J=7.4, 2H), 2.88(d, J=6.8, 2H), 3.80(s, 3H), 3.91(s, 3H), 4.42(t,J=7.5, 2H), 7.00(dd,J=2.0, J=8.1, 1H), 7.03(d,J=2.0, 1H), 7.13(d,J=8.1, 1H), 7.81(dd,J=5.6, J=8.2, 1H), 7.99(s, 1H), 8.39(ddd,J=1.4, J=2.1, J=8.2, 1H), 8.52(d,J=5.6, 1H), 8.90(d,J=2.1, 1H).

ESI/MS m/e: 530.3(M⁺+H, C₃₀H₃₅N₅O₄)

Example 54 Synthesis of ethyl 4-{7-iodo-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate

A sodium hydride (521 mg) was added to solution of N,N-dimethylformamide (60 mL) of ethyl 4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (4.07 g) in a small amount by each, and the mixture solution was stirred at room temperature for 30 minutes. A benzylchloromethylether (2.04 g) was added dropwise, and the mixture solution was further stirred for 2 hours. The solvent was distilled off under reduced pressure to separate the residue to ethyl acetate and aqueous layers. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (15-30% ethyl acetate/cyclohexane), to obtain the title compound (3.80 g, yield 71%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHZ,CDCl₃)δ(ppm): 1.25(t,J=7.1, 3H), 2.18(pent,J=7.0, 2H), 2.32(t,J=7.2, 2H), 4.12(q,J=7.1, 2H), 4.51(t,J=6.9, 2H), 4.65(s, 2H), 5.50(s, 2H), 7.22(s, 1H), 7.29(m, 1H), 7.33(m, 4H), 8.03(s, 1H).

ESI/MS m/e: 496.1(M⁺+H, C₂₀H₂₂IN₃O₄)

Example 55 Synthesis of ethyl-4-{7-(1-methylpyrazol-4-yl)-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate

The title compound was obtained by using ethyl 4-{7-iodo-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol in a similar manner to that in Example 28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 1.16(t,J=7.1, 3H), 2.16(pent,J=7.0, 2H), 2.33(t,J=7.2, 2H), 3.92(s,3H), 3.02(q,J=7.1, 2H), 4.49(t,J=6.7, 2H), 4.68(s, 2H), 5.56(s, 2H), 7.22(m, 1H), 7.28(m, 2H), 7.33(m, 2H), 7.54(s, 1H), 7.86(d,J=0.6, 1H), 8.03(s, 1H), 8.10(s, 1H).

ESI/MS m/e: 450.3(M⁺+H, C₂₄H₂₇N₅O₄)

Example 56 Synthesis of 4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid (Compound No. 2506)

Solution of concentrated hydrochloric acid (3 mL) of ethyl-4-{6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl) butanoate was heated for 1 hour to reflux. The solvent was distilled off under reduced pressure, and methanol solution (3 mL) of 2 mol/L ammonia was added to the residue. The solvent was distilled off under reduced pressure, and 1 mol/L of aqueous citric acid solution was added to the residue. A produced solid was extracted by filtration, washed with water and diethylether, and then dried under reduced pressure, to obtain the title compound (133 mg, yield 87%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 1.97(pent,J=7.0, 2H), 2.23(t,J=7.4, 2H), 3.91(s,3H), 4.50(t,J=6.8, 3H), 7.91(d,J=3.6, 1H), 8.04(s, 1H), 8.24(s, 1H), 12.11(s, 1H), 12.17(d,J=3.6, 1H).

ESI/MS m/e: 336.2 (M⁺+H, C₁₄H₁₄ClN₅O₃)

Example 57 Synthesis of 4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]]-N-[(4-methylphenyl)methyl]butanamide (Compound No. 2507)

A 4-methylbenzyl amine (29 mg) and a diisopropylethylamine (84 μm) were added to a solution of an N,N-dimethylformamide (1 mL) of 4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)-butanoate (40 mg). An o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (55 mg) was further added, and the mixture solution was stirred at room temperature overnight. An ethyl acetate and 1 mol/L of an aqueous citric acid solution were added to the reaction mixture, and separated to two layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure, to obtain the title compound (67 mg, quantitative yield). The compound was not further purified, but used for the following reaction. The ESI/MS data of the compound is given below.

ESI/MS m/e: 439.2 (M⁺+H, C₂₂H₂₃ClN₆O₂)

Example 58 Synthesis of 4-[6-(3,4-dimethoxyphenyl)-7-(1-methylpyrazol-4-yl)-4-oxo-7-(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl)methyl] butanamide (Compound No. 2345)

An N,N-dimethylformamide/water (2:1) solution (2 mL) of 4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo (3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl) methyl] butanamide (65 mg), 3,4-dimethoxyphenyl boric acid (81 mg), and potassium acetate (73 mg) was subjected to deaeration, followed by flushing with nitrogen gas. A small amount of [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride dichloro-methane (1:1) complex body was added thereto. The reaction mixture was heated at 160° C. for 45 minutes by using microwaves. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (5-8% methanol/ethyl acetate), and further purified by fraction HPLC to obtain the title compound (4.4 mg, yield 7%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time: 8.2 (min)

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 1.98(m,2H), 2.13(t,J=7.5, 2H), 2.29(2, 3H), 3.79(s, 3H), 3.82(s, 3H), 3.91(s, 3H), 4.18(s, 2H), 4.36(t,J=7.4, 2H), 6.98(m, 2H), 7.07(m, 4H), 7.12(d,J=7.9, 1H), 7.28(2, 1H), 7.66(s, 1H), 7.97(2, 1H).

ESI/MS m/e: 541.1(M⁺+H, C₃₀H₃₂N₆O₄)

Example 59 Synthesis of ethyl-4-(6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2508)

The title compound was obtained by using ethyl-4-β-amino-5-cyclopropyl-2-(ethoxycarbonyl)pyrolyl] butanoate hydrochloride in a similar manner to that in Example 45. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.74 (m, 2H), 1.00 (m, 2H) 1.13(t,J=7.2, 3H), 1.93-2.06(m, 3H), 2.31(t,J=7.4, 2H), 3.98(dd,J=7.2, J=14.2, 2H), 4.52(t,J=7.0, 2H), 6.00(s, 1H), 7.71(s, 1H), 11.76(brs, 1H).

ESI/MS m/e: 290.2(M⁺+H, C₁₅H₁₉N₃O₃)

Example 60 Synthesis of ethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2509)

A dichloromethane (40 mL) solution of an ethyl-4-(6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl) butanoate (1.58 g) and an N-iodosuccinimide (1.35 g) was stirred at room temperature for 2 hours. Water was added, and the mixture solution was further stirred for 30 minutes. A solid was extracted by filtration, washed by water and ethyl acetate, and dried under reduced pressure, to obtain the title compound (1.82 g, yield 80%). The filtration solution was separated to ethyl acetate and aqueous layers, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over a magnesium sulfate. The magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. A produced solid was extracted by filtration, washed with ethyl acetate, and dried under reduced pressure, to obtain the title compound (0.35 mg, yield 15%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.89(m, 2H), 1.08-1.15(m, 5H), 1.80(m, 1H), 2.01(m, 2H), 2.31(t,J=7.3, 2H), 3.96(dd,J=7.0, J=14.3, 2H), 4.57(t,J=7.2, 2H), 7.82(s, 1H), 12.00(brs, H).

ESI/MS m/e: 416.1(M⁺+H, C₁₅H₁₈IN₃O₃)

Example 61 Synthesis of ethyl-4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2510)

The title compound was obtained by using ethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl) butanoate and 3-pyridyl boric acid in a similar manner to that in Example 28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.31(m, 2H), 1.01(m, 2H) 1.13(t,J=7.2, 3H), 2.06-2.13(m, 3H), 2.40(t,J=7.3, 2H), 3.98(dd,J=7.2, J=14.2, 2H), 4.61(t,J=7.2, 2H), 7.43(ddd,J=0.8, J=4.8, J=7.9, 1H), 7.82(s, 1H), 8.01(dt,J=2.0, J=8.1,1H), 8.46(dd,J=1.7, J=4.7, 1H), 8.83(dd,J=0.8, J=2.3, 1H), 11.99(brs, 1H).

ESI/MS m/e: 367.2(M⁺+H, C₂₀H₂₂N₄O₃)

Example 62 Synthesis of 4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid (Compound No. 2363) hydrochloride

1M of aqueous lithium hydroxide solution (7.3 mL) was added to dioxane (25 mL) and water (10 mL) solution of ethyl-4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo [3,2-d]pyrimidin-5-yl) butanoate (1.06 g), and stirred at room temperature for 3 hours. 1M hydrochloric acid (10.2 mL) was added dropwise, and the solvent was distilled off under reduced pressure. An ethanol was added to a residue, a solid was extracted by filtration, washed with ethanol, and dried under reduced pressure, to obtain the title compound (1.10 g, quantitative yield). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.39(m, 2H), 1.10(m, 2H) 2.07(m, 2H), 2.18(m, 1H), 2.33(t,J=7.4, 2H), 4.63(t,J=7.3, 2H), 7.95(s, 1H), 8.10(dd,J=5.7, J=8.1, 1H), 8.82(m, 2H), 9.16(d,J=1.8, 1H), 12.26(brs, 1H).

ESI/MS m/e: 339.0(M⁺+H, C₁₈H₁₈N₄O₃HCl)

Example 63 Synthesis of 4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl))-N-[(4-methylphenyl)methyl]butanamide (Compound No. 2331)

A diisopropylethylamine (70 μL) and a 4-methylbenzyl amine (15 mg) were added to solution of N,N-dimethylformamide (1.5 mL) of 4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (30 mg) and O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg). The reaction solution was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to a residue, separated to two layers, and an aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over a sodium sulfate. The sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by fraction HPLC, to obtain the title compound (3.1 mg, yield 9%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

The HPLC retention time: 7.3 (min)

¹H-NMR(400 MHz,DMSO-d₆) δ(ppm): 0.27 (m, 2H), 0.93 (m, 2H), 2.01-2.11(m, 3H), 2.21-2.27(m, 5H), 4.21(d,J=5.9, 2H), 4.58(t,J=7.1, 2H), 7.10-7.15(m, 4H), 7.43(ddd,J=0.8, J=4.8, J=7.9, 1H), 7.82(s, 1H), 8.01(dt,J=2.0, J=8.1, 1H), 8.34(t,J=5.9, 1H), 8.46(dd,J=1.8, J=4.8, 1H), 8.84(dd,J=0.8, J=2.3, 1H).

ESI/MS m/e: 442.2(M⁺+H, C₂₆H₂₇NsO₂)

Example 64 Synthesis of ethyl-4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2511)

The title compound was obtained by using ethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol in a similar manner to that in Example 28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.51(m, 2H), 1.13(m, 5H), 1.91(m, 1H), 2.03(m, 2H), 2.31(t,J=7.3, 2H), 3.89(s, 3H), 3.97(dd,J=7.2, J=14.2, 2H), 4.58(t,J=7.0, 2H), 7.80(d,J=3.3, 1H), 7.83(d,J=0.7, 1H), 8.03(s, 1H), 11.87(brs, 1H).

ESI/MS m/e: 370.2(M⁺+H, C₁₉H₂₃N₅O₃)]

Example 65 Synthesis of 4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]butanoic acid (Compound No. 2364)

1M of aqueous lithium hydroxide solution (3.5 mL) was added to dioxane/water (4/1) solution (25 mL) of ethyl-4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (0.52 g) dropwise. The reaction solution was stirred at room temperature for 4 hours, and 1M hydrochloric acid (3.5 mL) was added thereto dropwise. The solvent was distilled off under reduced pressure, a residue was purified by column chromatography on silica gel (dichloromethane/methanol/acetate/water=240/30/3/2), a diethylether was added to the obtained solid, and finely pulverized. The solid was extracted by filtration, washed with diethylether, and dried under reduced pressure, to obtain the title compound (0.40 g, yield 84%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.51(m,2H), 1.12 (m,2H), 1.88-2.02(m,3H), 2.23(t,J=7.4,2H), 3.89(s,3H), 4.57(t,J=7.2,2H), 7.80(d,J=3.5,1H), 7.83(d,J=0.7,1H), 8.03(s,1H), 11.87(brs,1H).

ESI/MS m/e: 342.2 (M⁺+H, C₁₇H₁₉N₅O₃)

Example 66 Synthesis of 4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl)methyl]butanamide (Compound No. 2332)

A diisopropylethylamine (78 μL) and a 4-methylbenzyl amine (13 mg) were added to a solution of N,N-dimethylformamide (1.0 mL) of 4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]butanoate (30 mg) and 0-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (40 mg). The reaction solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, a residue was purified by fraction HPLC, to obtain the title compound (30 mg, yield 77%). The HPLC retention time and ESI/MS data of the compound are given below.

The HPLC retention time: 8.0 (min)

ESI/MS m/e: 445.3(M⁺+H, C₂₅H₂₈N₆O₂)

Example 67 Synthesis of 5-benzyl-7-(1-oxy(3-pyridyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 2499)

30% aqueous hydrogen peroxide solution (92 mg).was added to an acetic acid (2 mL) solution of 5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (31 mg), and the solution mixture was stirred at room temperature overnight. The reaction mixture was cooled to room temperature, purified by fraction HPLC, to obtain the title compound (19 mg, yield 58%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

The HPLC retention time: 5.8 (min)

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 5.64(s,2H), 7.24-7.35(m,5H), 7.46(m,1H), 8.00(m,2H), 8.10(m,1H), 8.34(s,1H), 9.11(s,1H), 12.25(brs,1H).

ESI/MS m/e: 319.3(M⁺+H, C₁₈H₁₄N₄O₂)

Example 68 Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl)-7-(5-methyl(1,2,4-oxadiazol-3-yl)-4-oxo-(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 2126)

A (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (105 mg) was dissolved in ethanol (2.5 mL), 35 mg of a hydroxylamine hydrochloride and a diisopropylethylamine (100 mg) were added thereto, and the solution mixture was stirred overnight under overheat reflux. The solvent was distilled off under reduced pressure, a dichloromethane (2.5 mL) and water (2.5 mL) were added thereto, and an organic layer was fractionally extracted. An aqueous layer was further extracted with dichloromethane (2.5 mL), an organic layer was combined, dried over sodium sulfate, and the solvent was distilled off under reduced pressure, to obtain a residue (113 mg). This residue was dissolved in dichloromethane (2 mL), acetate (18 mg), 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride (57 mg), and triethylamine (41 μL) were added thereto, and the solution mixture was stirred at 40° C. for 1 hour. The reaction solution was concentrated, and purified by fraction HPLC, to obtain the title compound (7.2 mg, yield 6%). The HPLC retention time and ESI/MS data of the compound are given below.

The HPLC retention time: 9.5 (min)

ESI/MS m/e: 476.9(M⁺+H, C₂₀H₂₁ClN₆O₄S)

Example 69 Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl)-7-(1,2,4-oxadiazol-3-yl)-4-oxo-(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 2513)

A (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (105 mg) was dissolved in ethanol (2.5 mL), 35 mg of a hydroxylamine hydrochloride and a diisopropylethylamine (100 mg) were added thereto, and the solution mixture was stirred overnight under overheat reflux. The solvent was distilled off under reduced pressure, a dichloromethane (2.5 mL) and water (2.5 mL) were added thereto, and an organic layer was fractionally extracted. An aqueous layer was further extracted with dichloromethane (2.5 mL), an organic layer was combined, dried over sodium sulfate, and the solvent was distilled off under reduced pressure, to obtain a residue (113 mg). Meanwhile N,N-dimethylformamide (40 mg) was dissolved in diethylether (1 mL), phosphorus oxychloride (84 mg) was added thereto, and the solution mixture was stirred at room temperature for 1 hour, to obtain an oily compound. The produced oily compound was washed with diethylether (1 mL) twice, and suspended to a solvent mixture (3 mL) of 1,4-dioxane and diethylether. This suspension was added to the residue, and stirred at room temperature for 2 hours. The reaction solution was concentrated, water (5 mL) and ethyl acetate (5 mL) were added thereto, and an organic layer was separated. An aqueous layer was further extracted with ethyl acetate (5 mL), an organic layer was combined and concentrated, and then purified by fraction HPLC, to obtain the title compound (1.9 mg, yield 1.6%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time: 9.1 (min).

ESI/MS m/e: 462.9(M⁺+H, C₁₉H₁₉ClN₆O₄S)

Example 70 Synthesis of (t-butoxy)-N-{2-[6-(3-hydroxyphenyl)-4-oxo-7-(3-pyridyl) (3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 2121)

A t-butoxy)-N-(2-{4-oxo-6-[3-(phenylmethoxy)phenyl]-7-(3-pyridyl) (3-hydropyrrolo[3,2-d]pyrimidin-5-yl)}ethyl}carboxyamide (8.0 mg) was dissolved in ethanol, and palladium carbon (20 mg) was added thereto. The reaction system was substituted by hydrogen, and stirred at 60° C. overnight under atmospheric hydrogen pressure. The reaction solution was cooled to room temperature, and the palladium carbon was filtered off. The filtration solution was concentrated, purified by fraction HPLC, to obtain the title compound (4.0 mg, yield 60%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time: 6.3 (min)

ESI/MS m/e: 448.0(M⁺+H, C₂₄H₂₅N₅O₄)

Examples 71 to 494

The following compounds of the present invention were synthesized according to any method of Example 1 to Example 70 by using corresponding starting materials and reaction agents. The ESI/MS data in the HPLC/mass spectrum analysis, the retention time of the compound in the HPLC analysis and purity under the following analysis conditions of each compound, and compound numbers corresponding to executed syntheses are summarized in Table 2. Compound numbers in the table represent compound numbers of Table 1 listed as the preferred specific examples. TABLE 2 Compound ESI/MS HPLC Purity Ex. no. no. Formula m/e min (%) Synthesis 71 19 C₁₉H₂₁N₅O₂ 352.2 5.7 96 Ex. 40 72 27 C₂₆H₂₅N₅O₃ 456.3 7.8 99 Ex. 40 73 29 C₁₇H₁₇N₅O₂ 324.2 3.3 99 Ex. 40 74 40 C₂₁H₁₅Cl₂N₇OS 484.2 7.7 98 Ex. 38 75 80 C₂₀H₁₄BrClN₆OS 503.2 6.8 100 Ex. 38 76 83 C₂₆H₁₉ClN₆S₂ 515.4 10.4 96 Ex. 38 77 212 C₁₉H₁₄ClN₅OS 395.4 11.7 86 Ex. 28 78 219 C₂₀H₁₈ClN₅O₂S 428.0 5.6 95 Ex. 35 79 230 C₂₁H₂₀ClN₅O₂S 442.4 6.5 100 Ex. 37 80 245 C₂₁H₂₀ClN₅O₂S 442.0 6.1 94 Ex. 35 81 254 C₂₂H₂₂ClN₅O₂S 456.1 6.9 95 Ex. 35 82 257 C₂₁H₂₃N₅O₂ 378.2 4.3 100 Ex. 36 83 263 C₂₀H₂₁N₅O₂ 364.2 10.0 96 Ex. 35 84 269 C₂₁H₁₈ClN₅O₂S 440.4 6.2 100 Ex. 37 85 280 C₂₂H₂₅N₅O₂ 392.2 5.4 100 Ex. 35 86 287 C₂₃H₂₂ClN₅O₂S 468.0 7.1 95 Ex. 35 87 288 C₂₂H₂₁ClN₄O₂S₂ 472.9 11.8 97 Ex. 35 88 297 C₂₃H₂₇N₅O₂ 406.2 12.9 98 Ex. 35 89 303 C₂₄H₂₄ClN₅O₂S 482.4 8.8 100 Ex. 37 90 321 C₁₉H₁₃ClF₃N₅O₂S 468.4 7.3 99 Ex. 37 91 330 C₂₃H₂₁N₅O₂ 400.5 5.0 99 Ex. 35 92 347 C₂₅H₁₈ClFN₄OS₂ 509.4 15.0 99 Ex. 37 93 348 C₂₄H₁₇ClFN₅O₂S 494.2 8.0 100 Ex. 37 94 361 C₂₆H₂₀ClN₅O₄S 534.0 9.4 78 Ex. 35 95 370 C₂₀H₁₃BrClF₃N₄O₃S 563.1 10.4 100 Ex. 35 96 492 C₂₃H₂₃ClN₆O₂S 483.1 10.8 93 Ex. 33 97 504 C₂₄H₂₅ClN₆O₂S 497.5 8.6 84 Ex. 33 98 536 C₃₀H₂₇ClN₆O₃S 587.4 9.0 79 Ex. 33 99 595 C₂₁H₂₅N₅O₂ 380.2 5.2 100 Ex. 35 100 596 C₂₂H₂₂ClN₅O₂S 456.1 6.9 98 Ex. 35 101 601 C₂₁H₂₅N₅O₂ 380.2 5.3 100 Ex. 35 102 602 C₂₂H₂₂ClN₅O₂S 456.1 7.1 94 Ex. 35 103 605 C₂₂H₂₉N₅O₂ 396.3 5.1 100 Ex. 35 104 615 C₂₂H₂₇N₅O₂ 394.1 7.5 99 Ex. 35 105 616 C₂₁H₂₆N₄O₃ 383.2 10.3 78 Ex. 28 106 617 C₂₁H₂₆N₄O₂S 399.1 11.6 87 Ex. 35 107 618 C₂₀H₂₆N₆O₂ 383.2 8.1 60 Ex. 28 108 627 C₂₂H₂₃ClN₄O₃S 459.3 15.0 95 Ex. 35 109 628 C₂₂H₂₃ClN₄O₂S₂ 475.2 15.7 100 Ex. 35 110 634 C₂₂H₂₇N₅O₂ 394.2 5.7 100 Ex. 53 111 641 C₂₃H₂₇N₅O₂ 406.2 5.9 100 Ex. 35 112 646 C₂₄H₂₄ClN₅O₂S 482.0 6.9 95 Ex. 35 113 657 C₂₁H₂₃N₅O₂ 378.3 4.3 97 Ex. 35 114 659 C₂₂H₂₀ClN₅O₂S 454.1 6.5 94 Ex. 35 115 664 C₂₃H₂₄ClN₅O₂S 470.2 9.1 99 Ex. 35 116 667 C₂₄H₂₉N₅O₂ 420.2 6.3 100 Ex. 36 117 668 C₂₅H₂₆ClN₅O₂S 496.0 8.3 8.5 80 Ex. 36 118 668 C₂₅H₂₆ClN₅O₂S 496.0 8.3 89 Ex. 36 119 673 C₂₅H₂₆ClN₅O₃S 512.0 6.6 98 Ex. 36 6.9 120 678 C₂₈H₃₂ClN₅O₂S 538.1 11.1 97 Ex. 36 121 689 C₂₅H₂₅ClN₆O₃S 525.0 5.9 78 Ex. 36 122 694 C₂₄H₂₉N₅O₂ 420.2 6.6 100 Ex. 35 123 696 C₂₅H₂₆ClN₅O₂S 496.0 8.5 98 Ex. 35 124 702 C₁₉H₂₁N₅O₃ 368.2 9.5 82 Ex. 35 125 704 C₂₀H₁₈ClN₅O₃S 444.0 5.4 87 Ex. 35 126 709 C₂₁H₂₁ClN₆O₂S 457.1 4.8 94 Ex. 35 127 713 C₂₁H₁₉ClN₆O₃S 471.0 5.2 85 Ex. 36 128 718 C₂₂H₂₀ClN₅O₄S 486.0 6.0 90 Ex. 35 129 723 C₂₄H₂₃N₅O₂ 414.5 5.0 98 Ex. 35 130 724 C₂₅H₂₀ClN₅O₂S 490.4 8.1 100 Ex. 37 131 729 C₂₅H₂₀ClN₅O₃S 506.0 8.0 90 Ex. 35 132 733 C₂₅H₂₅N₅O₂ 428.0 6.7 98 Ex. 35 133 734 C₂₆H₂₂ClN₅O₂S 504.0 8.5 94 Ex. 35 134 741 C₂₂H₂₀ClN₅O₂S 454.0 5.7 87 Ex. 35 135 760 C₂₀H₂₄N₆O₂ 381.1 5.1 98 Ex. 32 136 768 C₂₁H₂₁ClN₆O₂S 457.1 5.4 95 Ex. 32 137 770 C₂₀H₂₀ClN₅O₂S₂ 461.9 10.9 99 Ex. 32 138 776 C₂₄H₂₅ClN₆O₂S 497.0 7.7 95 Ex. 32 139 785 C₂₃H₂₂N₆O₂ 415.0 6.9 96 Ex. 32 140 795 C₂₃H₁₈ClN₅O₂S₂ 495.9 12.1 99 Ex. 32 141 801 C₂₄H₁₈ClFN₆O₂S 508.9 7.9 97 Ex. 32 142 802 C₂₄H₁₈ClFN₆O₂S 508.9 8.1 85 Ex. 32 143 803 C₂₄H₁₈Cl₂N₆O₂S 526.9 9.1 95 Ex. 32 144 804 C₂₅H₂₁ClN₆O₃S 520.9 7.7 98 Ex. 32 145 805 C₂₅H₂₁ClN₆O₂S 504.9 7.9 95 Ex. 32 146 806 C₂₅H₂₁ClN₆O₂S 504.9 8.2 85 Ex. 32 147 807 C₂₅H₂₁ClN₆O₂S 504.9 8.1 89 Ex. 32 148 808 C₂₄H₁₈Cl₂N₆O₂S 520.8 9.3 97 Ex. 32 149 809 C₂₄H₁₈Cl₂N₆O₂S 526.9 8.7 96 Ex. 32 150 810 C₂₄H₁₈ClFN₆O₂S 508.9 7.7 96 Ex. 32 151 811 C₂₅H₂₁ClN₆O₃S 520.9 8.9 93 Ex. 32 152 812 C₂₅H₂₁ClN₆O₃S 520.9 7.4 99 Ex. 32 153 912 C₂₂H₂₆N₄O₃ 349.5 9.5 91 Ex. 28 154 915 C₂₁H₂₅N₅O₃ 396.3 5.5 98 Ex. 28 155 917 C₂₀H₂₄N₄O₄ 385.3 10.9 66 Ex. 28 156 918 C₂₀H₂₄N₄O₃S 401.5 12.4 93 Ex. 28 157 948 C₁₈H₂₁ClN₄O₃S 409.2 11.4 82 Ex. 26 158 956 C₂₄H₂₅ClN₄O₃S 485.2 13.9 91 Ex. 26 159 968 C₂₃H₂₉ClN₄O₃S 477.3 12.9 95 Ex. 28 160 970 C₁₉H₁₉ClN₄O₃S 419.3 10.9 98 Ex. 27 161 972 C₂₃H₂₇ClN₄O₃S 475.2 11.4 83 Ex. 27 162 973 C₂₅H₃₀ClN₅O₃S 499.2 7.7 81 Ex. 27 163 974 C₂₅H₂₃ClN₄O₃S 495.5 10.9 98 Ex. 27 164 975 C₂₅H₂₂ClFN₄O₃S 513.2 11.1 95 Ex. 27 165 976 C₂₆H₂₅ClN₄O₄S 525.2 11.0 98 Ex. 27 166 977 C₂₅H₂₄ClN₅O₃S 510.2 7.9 28 Ex. 27 167 978 C₂₅H₂₂Cl₂N₄O₃S 529.2 11.5 95 Ex. 27 168 979 C₂₄H₂₂ClN₅O₃S 496.2 7.9 72 Ex. 27 169 980 C₂₄H₃₀ClN₅O₃S 487.3 7.5 92 Ex. 27 170 982 C₂₂H₂₇ClN₄O₃SSi 491.4 12.0 87 Ex. 27 171 983 C₂₃H₂₃ClN₄O₃S 471.3 10.5 92 Ex. 28 172 984 C₂₃H₂₂ClFN₄O₃S 489.2 10.9 85 Ex. 28 173 985 C₂₄H₂₂ClF₃N₄O₃S 539.2 12.1 92 Ex. 28 174 986 C₂₄H₂₂ClF₃N₄O₄S 555.3 12.2 93 Ex. 28 175 987 C₂₃H₂₂Cl₂N₄O₃S 505.1 11.6 95 Ex. 28 176 988 C₂₅H₂₅ClN₄O₄S 513.3 9.8 88 Ex. 28 177 989 C₂₉H₂₇ClN₄O₄S 563.3 12.5 91 Ex. 28 178 990 C₂₅H₂₇ClN₄O₅S 531.3 9.5 91 Ex. 28 179 991 C₂₅H₂₈ClN₅O₃S 514.2 7.3 79 Ex. 28 180 992 C₂₄H₂₅ClN₄O₃S 485.3 11.1 94 Ex. 28 181 993 C₂₇H₂₅ClN₄O₃S 521.6 — 81 Ex. 28 182 994 C₂₅H₂₇ClN₄O₃S 499.2 11.6 96 Ex. 28 183 995 C₂₁H₂₁ClN₆O₃S 473.2 8.0 22 Ex. 28 184 996 C₂₆H₂₈ClN₅O₄S 542.3 8.7 90 Ex. 28 185 997 C₂₉H₃₃ClN₄O₃S 553.3 14.0 88 Ex. 28 186 998 C₂₂H₂₂ClN₅O₃S 472.2 6.6 78 Ex. 28 187 999 C₂₂H₂₂ClN₅O₃S 472.4 8.0 97 Ex. 28 188 1001 C₂₁H₂₁ClN₄O₄S 461.1 12.5 84 Ex. 28 189 1002 C₂₁H₂₁ClN₄O₃S₂ 477.1 13.1 94 Ex. 28 190 1003 C₂₃H₂₄ClN₅O₄S 502.0 11.1 61 Ex. 28 191 1004 C₂₃H₂₄ClN₅O₄S 502.0 11.5 71 Ex. 28 192 1005 C₂₃H₂₄ClN₅O₄S 502.1 7.7 93 Ex. 28 193 1006 C₂₂H₂₁Cl₂N₅O₃S 506.0 12.8 90 Ex. 28 194 1007 C₂₂H₂₁ClFN₅O₃S 490.1 12.1 80 Ex. 28 195 1008 C₂₂H₂₁ClFN₅O₃S 490.1 12.8 94 Ex. 28 196 1009 C₂₆H₂₄ClN₅O₃S 522.0 10.4 54 Ex. 28 197 1010 C₂₄H₂₂ClN₅O₃S 496.4 14.7 88 Ex. 28 198 1011 C₂₃H₂₂ClFN₄O₃S 489.3 13.0 99 Ex. 28 199 1012 C₂₃H₂₂ClFN₄O₃S 489.4 13.3 96 Ex. 28 200 1013 C₂₂H₂₃ClN₄O₃S₂ 491.3 12.9 99 Ex. 28 201 1014 C₂₀H₂₁ClN₆O₃S 461.4 8.9 98 Ex. 28 202 1106 C₁₈H₁₉N₅O₂ 338.4 5.1 97 Ex. 40 203 1131 C₁₅H₁₅N₅O₂ 298.3 2.2 99 Ex. 40 204 1132 C₁₄H₁₃N₅O₂ 284.2 1.7 99 Ex. 40 205 1146 C₁₆H₁₅N₅O₂ 310.4 2.6 99 Ex. 40 206 1161 C₁₉H₁₅N₅O₂ 346.2 5.9 96 Ex. 40 207 1168 C₁₉H₂₃N₅O₂ 354.3 7.1 99 Ex. 40 208 1170 C₁₅H₁₄N₄O₃ 299.2 4.4 96 Ex. 39 209 1174 C₁₂H₁₀N₄O 227.2 2.4 100 Ex. 28 210 1175 C₁₂H₉ClN₄O 261.1 4.4 95 Ex. 41 211 1177 C₁₁H₈N₄O 213.1 5.0 99 Ex. 28 212 1179 C₁₈H₁₄N₄O 303.2 7.2 99 Ex. 39 213 1181 C₁₉H₁₅N₇O 358.1 3.6 100 Ex. 38 214 1182 C₂₃H₁₆ClN₇OS 474.0 6.8 67 Ex. 38 215 1183 C₂₂H₁₇ClN₈OS 477.1 7.7 100 Ex. 38 216 1184 C₂₃H₁₉N₇O 410.3 2.3 100 Ex. 38 217 1185 C₂₄H₁₈ClN₇OS 487.9 6.0 90 Ex. 38 218 1186 C₂₂H₁₇ClF₃N₇OS 520.1 8.1 100 Ex. 38 219 1206 C₂₀H₁₉ClN₆O₂S 443.1 6.7 97 Ex. 35 220 1216 C₂₁H₂₁ClN₆O₂S 457.0 8.6 87 Ex. 8 221 1217 C₂₂H₂₃ClN₆O₂S 471.1 7.6 83 Ex. 35 222 1228 C₂₃H₂₅ClN₆O₂S 485.2 8.2 96 Ex. 35 223 1236 C₂₅H₂₆ClN₅O₂S 497.9 8.4 96 Ex. 36 224 1237 C₂₄H₂₇ClN₆O₂S 499.2 8.5 99 Ex. 36 225 1243 C₂₅H₂₂ClFN₆O₂S 525.2 8.5 95 Ex. 35 226 1250 C₂₁H₂₃ClN₆O₂S 459.2 7.5 95 Ex. 35 227 1257 C₂₁H₂₃ClN₆O₂S 459.2 7.6 98 Ex. 35 228 1258 C₁₈H₂₄N₆O₂ 357.2 5.9 100 Ex. 53 229 1259 C₁₈H₂₃ClN₆O₂ 391.2 6.7 98 Ex. 50 230 1260 C₂₁H₂₇N₅O₂ 382.2 5.3 100 Ex. 53 231 1261 C₂₀H₂₈N₆O₂ 385.3 6.4 96 Ex. 35 232 1262 C₂₁H₃₀N₆O₂ 399.3 6.6 100 Ex. 35 233 1271 C₂₁H₂₈N₆O₂ 397.2 5.8 100 Ex. 35 234 1277 C₂₃H₂₈N₆O₃ 437.3 7.6 79 Ex. 53 235 1278 C₂₂H₂₆N₆O₃ 423.2 7.2 100 Ex. 53 236 1282 C₂₃H₂₅N₅O₂S 436.2 6.0 95 Ex. 53 237 1284 C₂₂H₂₆N₆O₂S 439.2 7.5 100 Ex. 53 238 1286 C₂₃H₂₈N₆O₂S 453.2 8.0 100 Ex. 53 239 1287 C₂₃H₂₄ClN₅O₃S 486.3 6.7 100 Ex. 67 240 1288 C₂₂H₂₅ClN₆O₂S 473.1 7.8 93 Ex. 35 241 1293 C₂₃H₂₇ClN₆O₂S 487.1 8.6 100 Ex. 28 242 1296 C₂₃H₂₈N₆O₂S 453.2 8.1 95 Ex. 53 243 1297 C₂₁H₂₅N₅O₂ 380.2 5.2 96 Ex. 53 244 1331 C₂₃H₂₇N₇O₂ 434.2 5.2 100 Ex. 53 245 1332 C₂₂H₂₈N₈O₂ 437.3 5.9 100 Ex. 53 246 1333 C₂₆H₃₂N₆O₄ 493.2 7.1 81 Ex. 53 247 1334 C₂₅H₂₈N₆O₄ 477.2 7.5 100 Ex. 53 248 1335 C₂₃H₂₅N₅O₃ 420.2 5.6 99 Ex. 53 249 1337 C₂₂H₂₆N₆O₃ 423.2 7.1 100 Ex. 53 250 1338 C₂₂H₂₆N₆O₂S 439.2 7.6 98 Ex. 53 251 1341 C₂₃H₂₈N₆O₂S 453.2 8.3 100 Ex. 53 252 1364 C₂₁H₂₃N₅O₂ 378.3 4.3 98 Ex. 35 253 1374 C₂₁H₂₁ClN₆O₂S 457.1 7.1 96 Ex. 35 254 1399 C₂₃H₂₅ClN₆O₂S 485.2 8.0 92 Ex. 36 255 1405 C₂₄H₂₉N₅O₂ 420.2 6.1 100 Ex. 36 256 1413 C₂₅H₂₆ClN₅O₂S 497.9 8.7 96 Ex. 36 257 1415 C₂₄H₂₇ClN₆O₂S 499.1 8.6 100 Ex. 36 258 1423 C₂₅H₃₁N₅O₂ 434.4 6.5 98 Ex. 36 259 1427 C₂₅H₂₉ClN₆O₂S 513.2 9.3 96 Ex. 36 260 1430 C₂₁H₂₁ClN₆O₂S 457.1 7.1 89 Ex. 35 261 1445 C₂₄H₂₇ClN₆O₂S 499.2 8.8 100 Ex. 36 262 1482 C₂₅H₃₁N₅O₂ 434.4 6.8 96 Ex. 35 263 1486 C₂₅H₂₉ClN₆O₂S 513.2 9.5 100 Ex. 36 264 1490 C₂₂H₂₇N₅O₂ 394.4 5.4 98 Ex. 35 265 1494 C₂₂H₂₅ClN₆O₂S 473.2 8.2 98 Ex. 35 266 1511 C₂₆H₂₃ClN₆O₂S 519.1 6.5 91 Ex. 33 267 1514 C₂₁H₁₉ClN₆O₂S 455.1 6.9 87 Ex. 35 268 1519 C₂₀H₂₃N₅O₂S 398.2 4.9 100 Ex. 36 269 1520 C₂₁H₂₀ClN₅O₂S₂ 474.0 5.3 98 Ex. 35 270 1522 C₂₄H₂₅ClN₆O₃S 513.1 4.2 100 Ex. 36 271 1530 C₂₅H₂₇ClN₆O₂S 512.9 5.4 92 Ex. 36 272 1533 C₂₀H₁₄ClF₄N₅O₂S 500.0 6.3 65 Ex. 35 273 1535 C₂₁H₁₃ClF₇N₅O₂S 568.0 7.7 96 Ex. 35 274 1549 C₂₅H₃₁N₅O₂ 434.2 6.8 100 Ex. 35 275 1553 C₂₅H₂₉ClN₆O₂S 513.2 9.5 90 Ex. 35 276 1554 C₂₆H₃₃N₅O₂ 448.2 7.5 100 Ex. 35 277 1558 C₂₆H₃₁ClN₆O₂S 527.2 10.3 95 Ex. 35 278 1566 C₂₄H₂₅ClN₆O₂S 497.2 8.3 97 Ex. 36 279 1589 C₂₃H₂₅F₂N₅O₂ 442.23 5.3 98 Ex. 36 280 1600 C₂₃H₂₃ClF₂N₆O₂S 521.2 7.8 98 Ex. 36 281 1623 C₂₇H₃₅N₅O₂ 462.2 7.5 100 Ex. 35 7.7 282 1647 C₂₄H₂₆F₃N₅O₂ 474.2 6.2 79 Ex. 36 6.5 283 1654 C₂₄H₂₄ClF₃N₆O₂S 553.2 9.1 99 Ex. 36 284 1660 C₂₅H₃₁N₅O₂ 434.3 6.5 99 Ex. 36 6.6 285 1661 C₂₅H₂₉ClN₆O₂S 513.2 9.3 98 Ex. 36 9.4 286 1673 C₂₂H₂₅N₅O₃ 408.2 4.5 100 Ex. 36 287 1679 C₂₂H₂₃ClN₆O₃S 487.1 6.4 95 Ex. 36 288 1682 C₂₈H₃₁ClN₆O₄S 583.2 6.9 96 Ex. 36 289 1691 C₂₈H₃₁ClN₆O₄S 583.2 6.9 98 Ex. 36 290 1693 C₂₇H₃₂ClN₇O₄S 586.2 8.4 95 Ex. 36 291 1695 C₂₇H₃₂ClN₇O₄S 586.2 8.6 95 Ex. 36 292 1696 C₂₈H₃₁ClN₆O₄S 583.1 7.0 99 Ex. 36 293 1697 C₂₇H₃₂ClN₇O₄S 586.2 8.6 94 Ex. 36 294 1698 C₂₆H₃₀ClN₇O₄S 572.1 7.8 93 Ex. 36 295 1699 C₂₇H₂₉ClN₆O₄S 569.1 6.2 98 Ex. 36 296 1700 C₂₆H₃₀ClN₇O₄S 572.2 7.8 92 Ex. 36 297 1715 C₂₉H₃₃ClN₆O₃S 581.2 6.3 93 Ex. 36 298 1719 C₂₇H₂₇ClN₆O₃S 551.1 5.2 96 Ex. 36 299 1721 C₂₈H₂₉ClN₆O₃S 565.2 5.7 93 Ex. 36 300 1739 C₂₇H₃₁ClN₆O₂S 539.2 4.7 90 Ex. 36 301 1748 C₂₈H₃₃ClN₆O₂S 553.2 5.1 95 Ex. 36 302 1751 C₂₈H₃₃ClN₆O₂S 553.2 5.2 96 Ex. 36 303 1753 C₂₉H₃₅ClN₆O₂S 567.2 5.5 89 Ex. 36 304 1758 C₂₇H₂₉ClN₆O₂S 537.1 4.7 96 Ex. 36 305 1778 C₂₅H₂₂F₃N₅O₂ 482.3 6.5 99 Ex. 36 306 1804 C₂₇H₂₁ClN₆O₂S 530.9 7.4 92 Ex. 36 307 1805 C₂₈H₂₃ClN₆O₂S 543.1 8.1 89 Ex. 36 308 1806 C₂₇H₂₂ClN₅O₂S 516.1 6.8 96 Ex. 35 309 1808 C₂₇H₂₂ClN₅O₂S 518.0 8.1 90 Ex. 36 310 1823 C₂₆H₂₃ClN₆O₂S 519.1 5.2 94 Ex. 36 311 1828 C₂₇H₂₅ClN₆O₂S 533.1 5.2 89 Ex. 36 312 1833 C₂₆H₂₁ClN₆O₂S 517.1 5.9 86 Ex. 36 313 1843 C₂₃H₂₅N₅O₃ 419.2 4.6 86 Ex. 36 314 1846 C₂₆H₂₇N₅O₂ 441.2 6.1 90 Ex. 36 315 1849 C₂₈H₃₆N₆O₄ 520.3 6.3 39 Ex. 36 316 1852 C₂₉H₃₈N₆O₄ 534.3 6.9 43 Ex. 36 317 1855 C₁₉H₁₈F₃N₅O₂ 406.2 4.4 98 Ex. 36 318 1860 C₁₉H₁₆ClF₃N₆O₂S 485.1 7.4 91 Ex. 36 319 1861 C₁₈H₁₆ClF₂N₅O₂ 408.2 4.9 36 Ex. 36 320 1865 C₂₀H₂₂ClN₅O₂ 400.3 4.6 60 Ex. 35 321 1868 C₂₁H₂₃N₅O₂ 378.3 4.4 97 Ex. 35 322 1885 C₂₀H₂₀F₃N₅O₂ 420.1 5.0 100 Ex. 36 323 1890 C₂₀H₁₈ClF₃N₆O₂S 499.1 7.7 98 Ex. 36 324 1891 C₂₄H₂₉N₅O₂ 420.2 6.3 100 Ex. 36 325 1894 C₂₄H₂₇ClN₆O₂S 499.2 9.0 100 Ex. 35 326 1899 C₂₁H₂₂F₃N₅O₂ 434.1 5.5 100 Ex. 36 327 1900 C₂₁H₂₀ClF₃N₆O₂S 513.1 8.2 98 Ex. 36 328 1913 C₂₁H₂₀N₆O₂ 389.1 4.1 100 Ex. 36 329 1915 C₂₁H₂₁Cl₂N₅O₂ 446.1 5.5 100 Ex. 36 330 2003 C₂₄H₂₇ClN₆O₂ 467.2 8.6 70 Ex. 53 331 2004 C₂₆H₂₅N₅O₂ 440.5 6.0 99 Ex. 35 332 2005 C₂₂H₂₃ClN₆O₂S 471.0 7.2 97 Ex. 32 333 2006 C₂₃H₂₃ClN₆O₂S 483.0 7.4 97 Ex. 32 334 2007 C₂₄H₂₁F₃N₆O₂ 483.3 7.0 99 Ex. 32 335 2008 C₂₄H₂₁F₃N₆O₃ 499.3 7.1 96 Ex. 32 336 2009 C₂₃H₁₇Cl₂N₇O₂S 526.0 6.5 90 Ex. 33 337 2010 C₂₅H₂₀ClFN₆O₂S 523.1 6.3 97 Ex. 32 338 2011 C₂₄H₂₁ClFN₇O₂S 526.1 7.9 97 Ex. 32 339 2012 C₂₄H₂₀ClN₇O₂S 506.1 4.0 81 Ex. 33 340 2013 C₂₅H₂₃F₃N₆O₃ 513.1 6.8 100 Ex. 32 341 2014 C₂₅H₂₇ClN₆O₂S 511.0 9.4 97 Ex. 32 342 2015 C₂₄H₂₈ClN₇O₂S 514.1 8.5 100 Ex. 32 343 2016 C₂₅H₂₁ClN₆O₂S 505.0 7.7 93 Ex. 32 344 2017 C₂₄H₂₁F₃N₆O₂ 483.2 6.8 100 Ex. 32 345 2018 C₂₄H₂₁F₃N₆O₂ 483.3 6.0 99 Ex. 32 346 2019 C₂₄H₂₆ClN₇O₃S 528.1 4.4 96 Ex. 33 347 2020 C₂₅H₂₈ClN₇O₃S 542.1 4.3 100 Ex. 33 348 2021 C₂₅H₂₈ClN₇O₂S 526.1 4.8 98 Ex. 33 349 2022 C₂₅H₃₂N₆O₂ 449.2 6.7 100 Ex. 32 350 2023 C₂₆H₂₉ClN₆O₂S 525.1 7.3 98 Ex. 32 351 2024 C₂₅H₃₀ClN₇O₂S 528.1 8.8 98 Ex. 33 352 2025 C₂₆H₂₉ClN₆O₂S 525.2 7.2 94 Ex. 33 353 2026 C₂₅H₃₀ClN₇O₂S 528.1 8.9 100 Ex. 32 354 2027 C₂₅H₂₇ClN₆O₃S 527.2 5.5 96 Ex. 33 355 2028 C₂₈H₂₉ClN₆O₂S 549.0 9.7 97 Ex. 32 356 2029 C₂₅H₂₀ClFN₆O₂S 523.1 5.8 97 Ex. 32 357 2031 C₂₄H₂₃FN₆O₂ 447.1 5.5 100 Ex. 32 358 2032 C₂₅H₂₀ClFN₆O₂S 523.1 6.3 98 Ex. 32 359 2033 C₂₄H₂₁ClFN₇O₂S 526.1 7.8 94 Ex. 32 360 2034 C₂₅H₁₉ClF₂N₆O₂S 541.0 6.7 96 Ex. 32 361 2036 C₂₄H₂₀ClF₂N₇O₂S 544.1 7.6 94 Ex. 32 362 2040 C₂₄H₂₂Cl₂N₆O₂ 497.3 6.6 100 Ex. 33 363 2042 C₂₅H₂₃F₃N₆O₂ 497.3 6.3 97 Ex. 33 364 2046 C₂₅H₂₃F₃N₆O₂ 497.3 6.6 98 Ex. 33 365 2049 C₂₅H₂₁ClF₃N₇O₂S 576.1 8.9 100 Ex. 32 366 2052 C₂₆H₂₀ClF₃N₆O₃S 589.0 7.6 98 Ex. 32 367 2053 C₂₅H₂₁ClF₃N₇O₃S 592.1 9.0 100 Ex. 32 368 2054 C₂₄H₂₄F₃N₇O₃ 516.2 8.0 100 Ex. 32 369 2056 C₂₆H₂₀ClF₃N₆O₃S 589.0 7.7 98 Ex. 32 370 2058 C₂₅H₂₁ClF₃N₇O₃S 592.1 9.1 100 Ex. 32 371 2060 C₂₆H₂₃ClN₆O₃S 535.1 6.3 99 Ex. 32 372 2062 C₂₆H₂₃ClN₆O₃S 535.1 6.2 96 Ex. 32 373 2063 C₂₅H₂₄ClN₇O₃S 538.1 7.7 91 Ex. 32 374 2064 C₂₅H₂₆N₆O₃ 459.1 5.3 100 Ex. 32 375 2065 C₂₆H₂₃ClN₆O₃S 535.1 6.1 99 Ex. 32 376 2067 C₂₅H₂₄ClN₇O₃S 538.1 7.7 91 Ex. 32 377 2068 C₂₇H₂₅ClN₆O₄S 565.1 5.8 89 Ex. 32 378 2069 C₂₆H₂₆ClN₇O₄S 568.1 7.0 63 Ex. 32 379 2070 C₂₇H₂₅ClN₆O₄S 565.1 6.5 87 Ex. 32 380 2071 C₂₆H₂₆ClN₇O₄S 568.1 7.7 94 Ex. 32 381 2072 C₂₆H₂₁ClN₆O₄S 549.1 6.2 96 Ex. 32 382 2073 C₂₅H₂₂ClN₇O₄S 552.0 7.5 90 Ex. 32 383 2078 C₂₆H₂₃ClN₆O₄S₂ 583.0 5.6 78 Ex. 32 384 2080 C₂₆H₂₇ClN₈O₂S 551.0 5.8 95 Ex. 33 385 2081 C₂₄H₂₀ClN₇O₂S 506.1 4.1 65 Ex. 33 386 2083 C₂₄H₂₀ClN₇O₂S 506.1 4.1 75 Ex. 32 387 2085 C₂₄H₁₉Cl₂N₇O₂S 540.0 5.0 88 Ex. 32 388 2086 C₂₃H₂₀Cl₂N₈O₂S 543.0 6.9 100 Ex. 33 389 2087 C₂₃H₁₉ClN₆O₃S 495.6 5.6 90 Ex. 32 390 2089 C₂₃H₁₉ClN₆O₂S₂ 511.0 5.8 94 Ex. 32 391 2093 C₂₆H₂₃ClN₆O₂S 519.1 6.5 98 Ex. 32 392 2094 C₂₆H₂₃ClN₆O₂S 519.1 6.5 98 Ex. 32 393 2095 C₂₇H₂₅ClN₆O₃S 549.1 6.4 100 Ex. 32 394 2096 C₂₇H₂₅ClN₆O₃S 549.1 6.4 94 Ex. 32 395 2097 C₂₆H₂₆ClN₇O₃S 552.1 7.9 94 Ex. 32 396 2098 C₂₅H₂₃ClFN₇O₂S 540.1 8.2 100 Ex. 32 397 2099 C₂₅H₁₈ClF₃N₆O₂S 558.9 9.6 96 Ex. 32 398 2100 C₂₃H₁₇Cl₂N₇O₂S 526.0 6.0 93 Ex. 33 399 2101 C₂₁H₁₆ClN₇O₂S₂ 497.9 6.4 85 Ex. 32 400 2102 C₂₄H₂₀ClF₂N₇O₂S 544.1 8.1 93 Ex. 33 401 2103 C₂₅H₂₂F₄N₆O₂ 515.3 6.7 97 Ex. 33 402 2105 C₂₅H₂₂F₄N₆O₂ 515.3 6.6 100 Ex. 33 403 2107 C₃₀H₂₈N₆O₂ 505.4 7.0 80 Ex. 33 404 2109 C₂₅H₂₁ClN₆O₂S 505.1 6.1 89 Ex. 33 405 2110 C₁₈H₂₁N₅O₃ 356.3 4.5 91 Ex. 28 406 2116 C₂₀H₂₆N₆O₃ 399.1 6.7 100 Ex. 28 407 2119 C₂₃H₃₂N₆O₃ 441.2 8.1 86 Ex. 28 408 2120 C₁₉H₂₂N₄O₄ 371.0 7.4 33 Ex. 70 409 2122 C₂₃H₂₆N₆O₄ 451.0 7.7 41 Ex. 70 410 2127 C₁₈H₁₉ClN₈O₃S 462.9 8.6 98 Ex. 28 411 2141 C₂₆H₂₈N₄O₄ 461.0 11.5 99 Ex. 10 412 2142 C₃₁H₃₁N₅O₄ 538.0 9.3 99 Ex. 28 413 2143 C₃₀H₃₂N₆O₄ 541.1 11.4 70 Ex. 28 414 2146 C₂₂H₂₂ClN₅O₃S 472.1 6.8 99 Ex. 35 415 2147 C₂₅H₂₀ClN₅O₃S 506.1 7.1 98 Ex. 35 416 2148 C₂₂H₂₂ClN₅O₃S 472.1 6.8 99 Ex. 35 417 2158 C₂₀H₂₃N₅O₂ 366.4 4.7 100 Ex. 49 418 2161 C₂₄H₂₉N₅O₂ 420.3 7.1 93 Ex. 63 419 2162 C₂₃H₃₀N₆O₂ 423.3 7.8 100 Ex. 63 420 2164 C₂₄H₂₈N₆O₂S 465.3 8.6 100 Ex. 53 421 2165 C₂₉H₃₃N₅O₄ 516.4 7.5 99 Ex. 53 422 2165 C₂₅H₂₇N₅O₃ 446.2 7.3 98.9 Ex. 53 423 2166 C₂₈H₃₄N₆O₄ 519.3 8.1 100 Ex. 53 424 2170 C₂₄H₂₈N₆O₃ 449.3 8.3 100 Ex. 53 425 2175 C₃₀H₃₁N₅O₃ 510.3 7.6 88 Ex. 63 426 2176 C₂₉H₃₂N₆O₃ 513.4 8.2 100 Ex. 63 427 2183 C₂₄H₂₄FN₅O₂S 466.3 6.2 98 Ex. 53 428 2184 C₂₃H₂₅FN₆O₂S 469.3 7.6 100 Ex. 53 429 2185 C₂₈H₃₀FN₅O₄ 520.3 6.1 99 Ex. 53 430 2186 C₂₇H₃₁FN₆O₄ 523.3 7.7 98 Ex. 53 431 2187 C₂₄H₂₄FN₅O₃ 450.3 5.9 98 Ex. 53 432 2188 C₂₃H₂₅FN₆O₃ 453.3 7.3 100 Ex. 53 433 2202 C₂₁H₂₅N₅O₂ 380.4 5.3 100 Ex. 49 434 2209 C₂₁H₁₉N₅O₂ 374.3 5.1 100 Ex. 49 435 2210 C₂₄H₂₂FN₅O₂ 432.2 7.0 93 Ex. 63 436 2211 C₂₃H₂₃FN₆O₂ 435.3 7.8 100 Ex. 63 437 2212 C₂₅H₂₂F₃N₅O₂ 482.3 7.2 79 Ex. 63 438 2224 C₂₅H₂₂F₃N₅O₃ 498.3 7.5 99 Ex. 63 439 2240 C₂₅H₂₄FN₅O₂ 446.3 7.0 96 Ex. 63 440 2241 C₂₄H₂₅FN₆O₂ 449.3 7.6 100 Ex. 63 441 2265 C₂₅H₃₁N₅O₂ 434.3 7.5 98 Ex. 63 442 2266 C₂₄H₃₂N₆O₂ 437.4 8.3 100 Ex. 63 443 2267 C₂₆H₂₉N₅O₂S 476.3 7.5 98 Ex. 53 444 2268 C₂₅H₃₀N₆O₂S 479.3 9.1 100 Ex. 53 445 2270 C₂₉H₃₁N₅O₄ 514.0 8.2 100 Ex. 53 446 2271 C₂₆H₂₉N₅O₃ 460.3 7.4 93 Ex. 53 447 2272 C₂₅H₃₀N₆O₃ 463.3 8.8 100 Ex. 53 448 2275 C₂₆H₃₃N₅O₂ 448.3 8.2 83 Ex. 63 449 2277 C₂₅H₃₄N₆O₂ 451.4 9.0 100 Ex. 63 450 2281 C₂₇H₃₁N₅O₂S 490.4 7.7 100 Ex. 53 451 2282 C₂₆H₃₂N₆O₂S 493.3 9.8 100 Ex. 53 452 2287 C₃₁H₃₇N₅O₄ 544.5 7.7 100 Ex. 53 453 2288 C₂₉H₃₆N₆O₄ 533.3 9.0 100 Ex. 53 454 2288 C₃₀H₃₈N₆O₄ 547.4 9.4 99 Ex. 53 455 2290 C₂₇H₃₁N₅O₃ 474.5 7.5 100 Ex. 53 456 2291 C₂₆H₃₂N₆O₃ 477.4 9.5 100 Ex. 53 457 2296 C₂₅H₂₅N₅O₂ 428.3 5.9 96 Ex. 63 458 2298 C₂₄H₂₂FN₅O₂ 432.3 5.8 95 Ex. 63 459 2299 C₁₉H₂₃N₅O₂ 354.4 4.6 100 Ex. 49 460 2300 C₁₈H₁₉N₅O₄ 370.3 2.2 100 Ex. 49 461 2301 C₁₈H₂₁N₅O₃ 356.4 2.5 100 Ex. 49 462 2305 C₂₅H₂₄FN₅O₂ 446.3 5.9 98 Ex. 63 463 2311 C₂₆H₂₄F₃N₅O₂ 496.3 7.1 98 Ex. 63 464 2325 C₂₆H₂₄F₃N₅O₃ 512.3 7.3 98 Ex. 63 465 2329 C₂₆H₂₇N₅O₂ 442.4 6.3 98 Ex. 63 466 2336 C₂₇H₂₅N₅O₂S 484.3 7.3 98 Ex. 53 467 2337 C₂₆H₂₆N₆O₂S 487.3 8.7 100 Ex. 53 468 2340 C₂₄H₂₆N₆O₂ 431.4 7.4 100 Ex. 53 469 2341 C₂₆H₂₇N₅O₂ 442.5 6.4 100 Ex. 53 6.6 470 2342 C₃₁H₂₉N₅O₂ 504.4 7.7 100 Ex. 53 7.9 471 2343 C₃₂H₂₉N₅O₃ 532.4 8.0 100 Ex. 53 472 2344 C₃₁H₃₁N₅O₄ 538.5 6.9 100 Ex. 53 473 2347 C₂₇H₂₅N₅O₃ 468.3 7.1 98 Ex. 53 474 2348 C₂₆H₂₆N₆O₃ 471.3 8.4 100 Ex. 53 475 2350 C₂₃H₂₃N₅O₃ 418.3 5.1 98 Ex. 63 476 2356 C₂₆H₂₇N₅O₂ 442.2 7.1 87 Ex. 63 477 2357 C₂₅H₂₈N₆O₂ 445.3 7.8 100 Ex. 63 478 2446 C₁₇H₁₁ClN₄O 323.2 4.5 100 Ex. 53 479 2448 C₁₇H₁₂N₄O₂ 305.3 2.5 100 Ex. 53 480 2452 C₁₈H₁₄N₄O₂ 319.3 4.2 100 Ex. 53 481 2459 C₁₈H₁₄N₄O₂ 319.3 2.9 100 Ex. 53 482 2469 C₁₆H₁₃N₅O 292.2 2.9 100 Ex. 53 483 2471 C₁₅H₁₀N₄OS 295.3 3.2 100 Ex. 53 484 2481 C₁₅H₁₀N₄O₂ 279.3 2.5 100 Ex. 53 485 2484 C₁₇H₁₀Cl₂N₄O 357.0 5.5 100 Ex. 53 486 2486 C₁₉H₁₆N₄O₃ 349.2 4.1 100 Ex. 53 487 2490 C₁₈H₁₅N₅O₃S 382.3 4.0 100 Ex. 53 488 2492 C₁₈H₁₂N₄O₃ 333.3 2.7 100 Ex. 53 489 2495 C₁₉H₁₃N₅O 328.3 5.1 100 Ex. 53 490 2500 C₂₆H₂₂N₄O₃ 439.0 7.5 94 Ex. 53 491 1562 C₂₄H₂₇N₅O₂ 418.5 5.7 99 Ex. 36 492 1895 C₂₅H₂₈N₆O₂ 445.5 5.7 99 Ex. 36 493 1875 C₂₁H₁₉F₆N₅O₂ 488.3 6.5 99 Ex. 36 494 2514 C₃₀H₃₁N₅O₃ 510.5 6.6 99 Ex. 36

Example 495

¹H-NMR(400 MHz, DMSO-d₆ or CDCl₃) of the compounds according to the present invention were measured. Data of chemical shift values (δ: ppm) and coupling constant (J: Hz) are shown in Table 3. Compound numbers in Table 3 designate compounds in Table 1 listed as preferred specific examples, and example numbers in the table denote examples of corresponding synthesized compounds Ex. Compound no. no. NMR data δ(ppm) Solvent 72 27 1.28-1.44(m, 2H), 1.76(m, 2H), 2.76(m, 1H), DMSO-d6 2.84-3.01(m, 2H), 3.15(m, 1H), 3.68(m, 1H), 3.87(d, J=12.96, 1H), 4.39(d, J=11.96, 1H), 4.62(m, 2H), 7.52(m, 2H), 7.63(m, 1H), 7.79(dd, J=5.38, J=8.06, 1H), 7.97(m, 3H), 8.24(s, 1H), 8.59(d, J=5.36, 1H), 8.78(d, J=8.32, 1H), 9.37(s, 1H), 12.24(brs, 1H). 73 29 0.00(m, 2H), 0.25(m, 2H), 2.28(m, 1H), 2.37(t, J=6.70, DMSO-d6 2H), 4.34(t, J=6.60, 2H), 7.58(dd, J=5.50, J=7.94, 1H), 7.69(d, J=3.92, 1H), 7.73(s, 1H), 7.86(s, 1H), 8.35(d, J=5.36, 1H), 8.58(d, J=8.28, 1H), 9.14(s, 1H), 12.02(brs, 1H). 75 80 3.96(m, 2H), 4.49(m, 1H), 4.88(m, 1H), 7.11(m, DMSO-d6 1H), 7.73-7.79(m, 2H), 7.83(m, 1H), 7.88(brs, 1H), 8.03(t, J=7.7, 1H), 8.18(d, J=8.5, 1H), 8.64(s, 1H), 10.00(brs, 1H), 12.29(brs, 1H). 202 1106 1.44(brs, 2H), 1.62(brs, 4H), 3.45(m, 4H), DMSO-d6 5.39(s, 2H), 7.81(dd, J=5.48, J=8.16, 1H), 7.98(s, 1H), 8.09(s, 1H), 8.60(d, J=5.40, 1H), 8.80(d, J=8.04, 1H), 9.39(s, 1H), 12.18(brs, 1H). 206 1161 5.36(s, 2H), 7.05(m, 1H), 7.31(t, J=7.56, 2H), DMSO-d6 7.58(d, J=7.56, 2H), 7.81(dd, J=5.24, J=8.16, 1H), 8.00(s, 1H), 8.18(s, 1H), 8.61(d, J=5.36, 1H), 8.80(d, J=8.04, 1H), 9.41(s, 1H), 10.37(s, 1H), 12.26(brs, 1H). 208 1170 1.19-1.23(m, 3H), 4.13-4.20(m, 2H), 5.30(s, 2H), DMSO-d6 7.79(m, 1H), 8.00(d, J=3.92, 1H), 8.15(d, J=4.16, 1H), 8.60(m, 1H), 8.76(d, J=8.07, 1H), 9.37(s, 1H), 12.28(brs, 1H). 209 1174 4.06(s, 3H), 7.84(dd, J=5.36, J=8.03, 1H), DMSO-d6 7.96(s, 1H), 8.16(s, 1H), 8.61(d, J=5.12, 1H), 8.84(d, J=7.75, 1H), 9.39(s, 1H), 12.21(brs, 1H). 212 1179 5.67(s, 2H), 7.13-7.36(m, 5H), 7.80(dd, J=5.35, DMSO-d6 J=8.03, 1H), 8.00(s, 1H), 8.36(s, 1H), 8.60(d, J=5.36, 1H), 8.83(d, J=8.07, 1H), 9.40(s, 1H), 12.29(brs, 1H).

Example 496 Determination of Inhibition of GSK-3 Activity

The reaction was initiated by adding 25 μL of phospho-glycogen synthase peptide-2 substrate solution [containing 6 μM phospho-glycogen synthase peptide-2, 20 μM ATP, 16 mM MOPS buffer (pH 7.0), 0.2 mM EDTA, 20 mM magnesium acetate, 0.1 μ Ci[γ-³³P]ATP (relative activity: approximately 110 TBq/mmol)] to 5 μL of each test compound using 5% dimethylsulfoxide as a solvent, and further adding 20 μL of GSK-3β enzyme solution [containing 10 mU recombinant human GSK-3β, 20 mM MOPS buffer (pH 7.0), 1 mM EDTA, 0.1% polyoxyethylene lauryl ether(23 Lauryl Ether; Brij 35), 5% glycerol, and 0.1% β-mercaptoethanol. After 20 minutes at room temperature, the reaction was terminated by the addition of the equivalent amount of 200 mM phosphoric acid solution. 90 μL of the reaction product was spotted onto a multiscreen PH plate (manufactured by Millipore) and washed with 100 mM phosphoric acid solution. The plate was dried, and 30 μL of MicroScint-O (manufactured by Packard BioScience) was added thereto. To evaluate inhibitory activity, cpm was counted using a scintillation counter. Here, Phospho GS Peptide 2 is an amino acid peptide having the following sequence: Tyr-Arg-Arg-Ala-Ala-Val-Pro-Pro-Ser-Pro-Ser-Leu-Ser-Arg-His-Ser-Ser-Pro-His-Gln-Ser(P)-Glu-Asp-Glu-Glu-Glu.

GSK-3 inhibitor activity values (IC₅₀ values) of the compounds according to the present invention were measured by the method described above. As a result, an inhibition activity of IC₅₀<100 nM was confirmed in compounds of compound numbers 263, 280, 287, 297, 615, 617, 618, 627, 629, 641, 668, 760, 785, 1014, 1183, 1206, 1216, 1217, 1228, 1237, 1243, 1250, 1257, 1271, 1286, 1287, 1288, 1293, 1296, 1374, 1399, 1405, 1415, 1423, 1427, 1430, 1445, 1494, 1514, 1549, 1553, 1566, 1589, 1600, 1647, 1654, 1660, 1661, 1679, 1693, 1695, 1715, 1721, 1890, 1900, 2007, 2008, 2010, 2011, 2012, 2013, 2014, 2015, 2017, 2022, 2026, 2031, 2032, 2033, 2034, 2036, 2040, 2042, 2046, 2049, 2053, 2054, 2058, 2062, 2063, 2064, 2065, 2067, 2068, 2069, 2070, 2071, 2072, 2073, 2078, 2080, 2083, 2085, 2086, 2095, 2097, 2098, 2102, 2103, 2105, 2107, 2212, 2224, 2311.

Also, an inhibition activity of 20 nM<IC₅₀<100 nM was confirmed in compounds of compound numbers 40, 217, 219, 230, 245, 269, 288, 303, 595, 596, 601, 602, 616, 626, 628, 634, 646, 657, 659, 664, 667, 668, 673, 689, 694, 696, 723, 733, 734, 741, 768, 770, 776, 793, 795, 801, 802, 803, 804, 805, 806, 807, 809, 810, 812, 915, 1182, 1186, 1236, 1260, 1277, 1278, 1282, 1284, 1335, 1337, 1338, 1341, 1364, 1413, 1482, 1486, 1490, 1519, 1520, 1533, 1554, 1558, 1623, 1673, 1682, 1691, 1696, 1700, 1719, 1739, 1748, 1751, 1753, 1758, 1778, 1806, 1808, 1846, 1849, 1852, 1855, 1865, 1868, 1885, 1894, 1899, 2004, 2005, 2006, 2016, 2018, 2019, 2020, 2021, 2024, 2025, 2027, 2029, 2052, 2056, 2060, 2081, 2087, 2089, 2094, 2099, 2100, 2101, 2146, 2147, 2148, 2161, 2175, 2183, 2184, 2210, 2211, 2240, 2241, 2265, 2266, 2275, 2296, 2298, 2305, 2325, 2329, 2331, 2332, 2336, 2337, 2341, 2342, 2347, 2348, 2350, 2448, 2486, 2492.

Also, an inhibition activity of 100 nM<IC₅₀<1 μM was confirmed in compounds of compound numbers 81, 84, 254, 257, 320, 321, 330, 348, 361, 492, 504, 536, 550, 605, 678, 684, 702, 704, 709, 713, 718, 724, 729, 808, 811, 917, 918, 946, 1001, 1002, 1007, 1008, 1178, 1181, 1184, 1185, 1258, 1259, 1261, 1262, 1297, 1331, 1333, 1334, 1511, 1522, 1530, 1535, 1697, 1804, 1805, 1823, 1833, 1843, 1860, 1861, 1891, 1913, 1915, 2003, 2023, 2028, 2093, 2096, 2109, 2116, 2158, 2162, 2164, 2165, 2166, 2170, 2176, 2186, 2187, 2188, 2202, 2209, 2264, 2267, 2268, 2269, 2270, 2271, 2272, 2277, 2281, 2282, 2288, 2290, 2291, 2292, 2299, 2300, 2340, 2344, 2345, 2356, 2357, 2445, 2446, 2452, 2459, 2469, 2471, 2481, 2484, 2490, 2495.

Compound numbers designate compounds in Table 1 listed as preferred specific examples.

As described above, the pyrrolopyrimidine derivatives according to the present invention exhibit strong inhibitory activity against GSK-3. Therefore, the pyrrolopyrimidine derivatives according to the present invention have been found to be inhibitors of GSK-3 activity to be used in prevention and/or treatment of various diseases associated with GSK-3, which are clinically applicable compounds.

Example 493 Preparation of Tablets

Tablets each comprising the following ingredients were prepared. Compound (Example 1) 50 mg Lactose 230 mg  Potato starch 80 mg Polyvinylpyrrolidone 11 mg Magnesium stearate  5 mg

The compound of the present invention (the compound prepared in Example 1), lactose, and potato starch were mixed, homogenously wetted with 20% ethanol solution of polyvinylpyrrolidone, passed through a 20 mesh sieve, dried at 45° C., and passed through again a 15 mesh sieve to obtain granules. The thus obtained granules were mixed with magnesium stearate and compressed into tablets.

Reference Example 15 Synthesis of N-{2-[4-chloro-6-(3-chloro(2-thienyl))-7-iodopyrrolo[3,2-d]pyrimidin-5-yl] -ethyl}-2,2,2-trifluoroacetoamide

A phosphorus oxychloride (3.0 mL) solution of N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide (333 mg) was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, and excess phosphorus oxychloride was distilled off under reduced pressure. A residue was dried in vacuo to obtain a crude product of the title compound as a brown oily compound. The product was not purified, but used for the following reaction. The ESI/MS data of the compound is given below.

ESI/MS m/e: 535.2(M⁺+H, C₁₄H₈Cl₂F₃IN₄OS)

Reference Example 16 Synthesis of N-{2-[7-bromo-4-chloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetoamide

A crude product of the title compound was obtained by using N-{2-[7-promo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide (333 mg) in a similar manner to that in Reference Example 15. The ESI/MS data of the compound is given below.

ESI/MS m/e: 489.0(M⁺+H, C₁₄H₈BrCl₂F₃N₄OS)

Reference Example 17 Synthesis of N-{2-[4,7-dichloro-6-(3-chloro(2-thienyl))pyrrolo [3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetoamide

A crude product of the title compound was obtained by using N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide (333 mg) in a similar manner to that in Reference Example 15. The ESI/MS data of the compound is given below.

ESI/MS m/e: 443.4(M⁺+H, C₁₄H₈Cl₃F₃N₄OS)

INDUSTRIAL APPLICABILITY

The pyrrolopyrimidinone derivatives of Formula (I) according to the present invention and its pharmaceutically acceptable salts have GSK-3 inhibitory activity and are used as effective ingredients of pharmaceutical products. Therefore, pharmaceutical agents containing these compounds as effective ingredients are expected as promising therapeutic drugs or preventive drugs in GSK-3 mediated diseases including diabetes, diabetic complications, Alzheimer's disease, neurodegenerative diseases manic depression, traumatic cerebrospinal injury, alopecia, inflammatory diseases, cancer and immunodeficiency. 

1. A compound represented by the formula (I) or its pharmaceutically acceptable salts:

wherein A¹ represents a single bond, or an acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms that links a nitrogen atom bonded to A¹ with A² on the same or different carbon atom; A² represents a single bond or represents a group that links A¹ with G¹ in the form of A¹-C(═O)-G¹, A¹—C(═O)—O-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹-C(═S)—NR¹⁰²-G¹, A¹—C(═NR¹⁰³)-G¹, A¹-O-G¹, A¹-O—C(═O)-G¹, A¹-NR¹⁰⁴-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁶—S(═O)₂-G¹, A¹-NR¹⁰⁷—C(═O)—O-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, A¹-NR¹¹⁰C(═S)-G¹, A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹, A¹—S-G¹, A¹-S(═O)-G¹, A¹-S(═O)₂-G¹, A¹-S(═O)₂—NR¹³-G¹, A¹-CR¹¹⁴═CH-G¹, A¹-CR¹¹⁵═CF-G¹, A¹-CH═CR¹¹⁶-G¹, or A¹—CF═CR¹¹⁷-G¹; G¹ represents a single bond or represents a divalent group which is obtainable by removing two hydrogen atoms from any one of an optionally substituted alicyclic hydrocarbon having 3 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon having 6 to 14 carbon atoms, and an optionally substituted heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, A³ represents a single bond or represents an optionally substituted divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms that links G¹ with A⁴ on the same or different carbon atom; A⁴ represents a single bond or represents a group that links A³ with G² in the form of A³-C(═O)-G², A³-C(═O)—O-G², A³-C(═O)—NR¹²¹-G², A³-C(═S)—NR¹²²-G², A³-C(═NR¹²³)-G², A³-O-G², A³-O—C(═O)-G², A³-NR¹²⁴-G², A³-NR¹²⁵—C(═O)-G², A³-NR¹²⁶—S(═O)₂-G², A³-NR¹²⁷—C(═O)—O-G², A³—NR¹²⁸—C(═O)—NR¹²⁹-G², A³-NR¹³⁰—C(═S)-G², A³-NR¹³¹—C(═S)—NR¹³²-G², A³-S-G², A³-S(═O_)-G², A³-S(═O)₂-G², A³-S(═O)₂—NR¹³³-G² or A³-S(═O)₂—O-G²; G² is a hydrogen atom, an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring; A⁵ represents a single bond or —NR²⁰¹—; R² is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring; A⁶ represents a single bond or represents a group that links R³ with a carbon atom of a pyrrole ring to which A⁶ is bonded, in the form of R³—NR³⁰¹-pyrrole ring, R³—C(═O)-pyrrole ring, R³—NR³⁰²—C(═O)-pyrrole ring, R³—NR³⁰³—C(═S)-pyrrole ring, R³—NR³⁰⁴—C(═O)—NR³⁰⁵-pyrrole ring, R³—C(═O)—NR³⁰⁶-pyrrole ring, R³—NR³⁰⁷—CH═N-pyrrole ring, R³—C(═O)—O-pyrrole ring, R³—O—C(═O)-pyrrole ring, R³—O-pyrrole ring, R³—S-pyrrole ring, R³—S(═O)-pyrrole ring, R³—S(═O)₂-pyrrole ring, R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring, R³—C≡C-pyrrole ring, or R³—S(═O)₂—C≡C-pyrrole ring; R³ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an optionally substituted saturated acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring; A⁶-R³ may be a combination wherein A⁶ represents a group that links a carbon atom of a pyrrole ring to which A⁶ is bonded, with R³ in the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring or R³—C≡C-pyrrole ring, and R³ represents a trimethylsilyl group, a formyl group, an optionally substituted acyl group having 2 to 7 carbon atoms, a carboxyl group, a alkoxycarbonyl group having 2 to 7 carbon atoms, a carbamoyl group, an optionally substituted alkylcarbamoyl group having 2 to 7 carbon atoms, or a cyano group; R¹⁰¹-R¹¹⁷, R¹²¹-R¹³³, R²⁰¹ and R³⁰¹-R³⁰⁹ are each independently a hydrogen atom or an aliphatic hydrocarbon group having 1 to 4 carbon atoms; with the proviso that when both of A¹ and A³ represent an acyclic aliphatic hydrocarbon group, then at least either one of A² or G¹ is not a single bond.
 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms.
 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A¹ is —(CH₂)₂— or (CH₂)₃—.
 4. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein A² represents a group other than a single bond.
 5. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein A² represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—.
 6. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein A² represents —C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.
 7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein both of A¹ and A² represent a single bond.
 8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein combination of G¹, A³, A⁴, and G² is any of the combinations of 1 to 10 in the following table. Combination G¹ A³ A⁴ G² 1 Group other Single bond Single bond Hydrogen atom than single bond 2 Single bond Group other Single bond Hydrogen atom than single bond 3 Group other Single bond Single bond Group other than single than hydrogen bond atom 4 Single bond Group other Single bond Group other than single than hydrogen bond atom 5 Group other Single bond Group other Group other than single than single than hydrogen bond bond atom 6 Single bond Group other Group other Group other than single than single than hydrogen bond bond atom 7 Group other Group other Single bond Group other than single than single than hydrogen bond bond atom 8 Group other Group other Group other Group other than single than single than single than hydrogen bond bond bond atom 9 Group other Group other Group other Hydrogen atom than single than single than single bond bond bond 10 Single bond Single bond Single bond Hydrogen atom


9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹ represents a group other than a single bond, A³ and A⁴ represent a single bond, and G² represents a hydrogen atom.
 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹ and A⁴ represent a single bond, A³ represents a group other than a single bond, and G² represents a hydrogen atom.
 11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹ represents a group other than a single bond, A³ and A⁴ represent a single bond, and G² represents a group other than a hydrogen atom.
 12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹ and A⁴ represent a single bond, A³ represents a group other than a single bond, and G² represents a group other than a hydrogen atom.
 13. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein A³ represent an alkylene group having 1 to 3 carbon atoms.
 14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹ and A⁴ represent a group other than a single bond, A³ represents a single bond, and G² represents a group other than a hydrogen atom.
 15. The compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein A⁴ represents —C(═O)—, —C(═O)—NH—, —O—, or —NH—C(═O)—.
 16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹ represents a single bond, A³ and A⁴ represent a group other than a single bond, and G² represents a group other than a hydrogen atom.
 17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹ and A³ represent a group other than a single bond, A⁴ represents a single bond, and G² represents a group other than a hydrogen atom.
 18. The compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein A³ represent an alkylene group having 1 to 3 carbon atoms.
 19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹, A³ and A⁴ represent a group other than a single bond, and G² represents a group other than a hydrogen atom.
 20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein A⁴ represents —O—.
 21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹, A³ and A⁴ represent a group other than a single bond, and G² represents a hydrogen atom.
 22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G¹, A³ and A⁴ represent a single bond, and G² represents a hydrogen atom.
 23. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein A² represents —NH—(C═O)— or —NH—(C═O)—NH—, G¹ represents a single bond, and A³ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms.
 24. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein A² represents —NH—(C═O)—, —NH—(C═O)—NH—, —NH—, or —C(═O)—NH—, and G¹ represents a group other than a single bond.
 25. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein A² represents a single bond, and G¹ represents an optionally substituted heterocyclic group, with the proviso that when the heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, then the 5 or 6 membered monocyclic heterocyclic group of G¹ is substituted or the A³-G² portion represents those other than a hydrogen atom.
 26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein G¹ represents an optionally substituted aromatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group having 7 to 10 carbon atoms, or an optionally substituted heterocyclic group, with the proviso that when the aromatic hydrocarbon group of G¹ is a phenyl group, or the heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, then the phenyl group or the 5 or 6 membered monocyclic heterocyclic group of G¹ is substituted, or the A³-G² portion represents those other than a hydrogen atom.
 27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein G¹ and A⁴ represent a single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, G² represents an optionally substituted alicyclic hydrocarbon group having 5 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group, or an optionally substituted heterocyclic group.
 28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein G¹ represents a single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, and A⁴ represents —C(═O)—, —C(═O)—NR¹²¹—, —C(═S)—NR¹²²—, —C(═NR¹²³)—, —O—C(O)—, —NR¹²⁵—C(═O)—, —NR¹²⁶—S(═O)₂—, —NR¹²⁷—C(═O)—O—, —NR¹²⁸—C(═O)—NR¹²⁹—, —NR¹³⁰—C(═S)—, —NR¹³¹—C(═S)—NR¹³²—, —S—, —S(═O)—, —S(═O)₂—, —S(═O)₂—NR¹³³—, or —S(═O)₂—O—.
 29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein A⁵ represents a single bond.
 30. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R² represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group.
 31. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R² represents an acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted phenyl group, or an optionally substituted heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom, or a sulfur atom, in the ring.
 32. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R² represents a cyclopropyl group, cyclobutyl group, cyclopropylmethyl group, methyl group, ethyl group, vinyl group, isopropyl group, or 2-methyl-1-propenyl group.
 33. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R² represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, or phenyl group; any of which may be further substituted by one or more of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an acyl group having 2 to 4 carbon atoms, a hydroxy group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a fluorine atom, or a chlorine atom.
 34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 33, wherein A³ represents a single bond.
 35. The compound or a pharmaceutically acceptable salt thereof according to claim 34, wherein R³ represents an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms.
 36. The compound or a pharmaceutically acceptable salt thereof according to claim 34, wherein R³ represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, or phenyl group; any of which may be further substituted by one or more of an alkyl group having 1 to 4 carbon atoms.
 37. The compound or a pharmaceutically acceptable salt thereof according to claim 34, wherein R³ represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; a pyrazolyl group; or N-methylpyrazolyl group.
 38. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein A⁶ represents a single bond.
 39. The compound or a pharmaceutically acceptable salt thereof according to claim 32, wherein A⁶ represents a single bond, and R³ represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; a pyrazolyl group; or N-methylpyrazolyl group.
 40. The compound or a pharmaceutically acceptable salt thereof according to claim 33, wherein A⁶ represents a single bond, and R³ represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; a pyrazolyl group; or N-methylpyrazolyl group.
 41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 23 to 28, wherein both of A⁵ and A⁶ represent a single bond.
 42. The compound or a pharmaceutically acceptable salt thereof according to claim 41, wherein R² represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group, and R³ represents an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms or an optionally substituted heterocyclic group.
 43. The compound or a pharmaceutically acceptable salt thereof according to claim 41, wherein R² represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted phenyl group, or an optionally substituted heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring, and R³ represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, or a phenyl group, any of which may be further substituted by one or more of a C₁-C₄ alkyl group.
 44. The compound or a pharmaceutically acceptable salt thereof according to claim 41, wherein R² represents a cyclopropyl group, methyl group, ethyl group, vinyl group, isopropyl group, isobutyl group, or 2-methyl-1-propenyl group, and R³ represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; pyrazolyl group; or N-methylpyrazolyl group.
 45. The compound or a pharmaceutically acceptable salt thereof according to claim 41, wherein R² represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, or a phenyl group, any of which may be further substituted by one or more of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a chlorine atom, and R³ represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; pyrazolyl group; or N-methylpyrazolyl group.
 46. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 45; and a pharmaceutically acceptable carrier.
 47. A GSK-3 inhibitor comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to
 45. 48. An agent for treating or preventing a GSK-3-mediated disease, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to
 45. 49. The agent for treating or preventing according to claim 48, wherein the GSK-3-mediated disease is selected from the group consisting of diabetes, diabetic complications, Alzheimer's disease, neurodegenerative disease, manic depressive psychosis, traumatic brain injury, alopecia, inflammatory disease, cancer, and immunodeficiency.
 50. A compound represented by the formula (Ic):

wherein A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², R³, and X are as defined in the formula (I); and Q represents an optionally substituted acyl group having 2 to 10 carbon atoms, an optionally substituted alkoxymethyl group having 2 to 10 carbon atoms, or an optionally substituted benzyl group. 